JP2021004264A - Composition and method for combination antiviral treatment - Google Patents

Abstract

To provide a novel combination of orally active drugs for the treatment of a patient infected with a specific virus (e.g., HIV).SOLUTION: The present invention provides a therapeutic combination of [2-(6-amino-purin-9yl)-1-methyl-ethoxymethyl]-phosphonic acid di-isopropoxycarbonyl oxymethyl ester (Tenofovir disoproxil fumarate, Viread (R)) and (2R, 5S, cis)-4-amino-5-fluoro-1-(2 hydroxymethyl-1, 3-oxathiolane-5-yl)-(1H)- pyrimidine-2-one (emtricitabine,(-)-cis FTC EmtrivaTM, and also provides their physiologically functional derivatives. The combination may be useful in the treatment of HIV infections, including infections with HIV variants that are resistant to nucleoside inhibitors and/or non-nucleoside inhibitors.SELECTED DRAWING: None

Description

This non-provisional application claims the interests of provisional applications 60/440, 246 and 60/440, 308 (both filed January 14, 2003). These provisional applications are incorporated herein by reference.

(Field of invention)
The present invention relates generally to combinations of compounds having antiviral activity, and more specifically to combinations of compounds having anti-HIV properties. In particular, the present invention relates to chemically stable combinations of structurally diverse antiviral agents.

(Background of invention)
Human immunodeficiency virus (HIV) infections and related diseases are major public health problems worldwide. Human immunodeficiency virus type 1 (HIV-1) encodes at least three enzymes required for viral replication: reverse transcriptase (RT), protease (Prt), and integrase (Int). Drugs that target reverse transcriptases and proteases are widely used and have shown efficacy, especially when used in combination, but the development of toxic and resistant strains limits their usefulness. (Palella et al., N. Engl. J. Med. (1998) 338: 853-860; Richman, DD Nature (2001) 410: 995-1001). Human immunodeficiency virus type 1 (HIV-1) protease (Prt) is essential for viral replication and is an effective target for licensed antiviral drugs. This HIV Prt cleaves viral Gag and Gag-Pol polyproteins to produce viral structural proteins (p17, p24, p7 and p6) and three viral enzymes. Combination therapy with RT inhibitors has proven to be highly effective in suppressing viral replication to unquantifiable levels over a sustained period of time. In addition, combination therapy with RT inhibitors and Prt inhibitors (PIs) has shown synergistic effects in suppressing HIV replication. Unfortunately, a high proportion (typically 30% to 50%) of patients now develop drug resistance, comply with complex dosing regimens, pharmacokinetic interactions, toxicity, and efficacy. The combination treatment is failing due to lack. Therefore, there is a need for novel HIV-1 inhibitors that are active against mutant HIV strains, have a clear resistance profile, fewer side effects, less complex dosing schedules, and are orally active. .. In particular, there is a need for a less cumbersome dosing regimen (eg, optimally, oral administration once daily with as few pills as possible).

The use of a combination of compounds can reduce toxicity and result in an equivalent high viral effect, or increased drug efficacy. Less overall drug administration can reduce the frequency of development of drug-resistant variants of HIV. Many different methods have been used to test the effects of combinations of compounds that act together in different assay systems (Furman, WO 02/068058). Less dosing anticipates better patient compliance if the pill loading is reduced and the dosing schedule is simplified, and if necessary, synergies between the compounds occur (Loveday, C.I. "Nucleoside compliance
"Transcriptase inhibitor response" (2001) JAIDS Journal of Acquired ImmunoDeficiency Syndromes 26: S10-S24). AZT (zidovudine ^TM , 3'-azido, 3'-deoxythymidine) is combined with drugs that act in HIV-1 replication steps other than reverse transcription, including recombinant soluble CD4 castanospermin and recombinant interferon α. And demonstrate synergistic antiviral activity in vitro. However, it should be noted that compound combinations can cause increased cytotoxicity. For example, AZT and recombinant interferon α have an elevated cytotoxic effect on normal human bone marrow progenitor cells.

The chemical stability of antiviral combinations is an important aspect of co-formulation success, and the present invention provides examples of such combinations.

A novel combination of oral active drugs for the treatment of patients infected with a particular virus (eg, HIV), which provides enhanced therapeutic safety and efficacy, confer lower resistance, and There is a need for combinations that anticipate higher patient compliance.

(Gist of the invention)
The present invention provides combinations of antiviral compounds, in particular compositions and methods for inhibiting HIV. In an exemplary aspect, the invention comprises a composition comprising tenofovir disoproxil fumarate and emtricitabine having anti-HIV activity. The composition of tenofovir DF and emtricitabine is either chemically stable and synergistic, and / or reduces the side effects of one or both of tenofovir DF and emtricitabine. Referencing lower pill loadings and simplified dosing schedules is likely to increase patient compliance.

The present invention relates to [2- (6-amino-purine-9-yl) -1-methyl-ethoxymethyl] -phosphonate diisopropoxycarbonyloxymethyl ester fumarate (tenofovir disoproxil fumarate, tenofovir DF, TDF). , Viread®) and (2R, 5S, cis) -4-amino-5-fluoro-1- (2-hydroxymethyl-1,3-oxathiolan-5-yl)-(1H) -pyrimidine- 2-one (emtricitabine, Emtriva ^TM, (-) - cis FTC) including infections in the therapeutic combinations, and HIV infection (nucleoside inhibitors and / or HIV mutants resistant to non-nucleoside inhibitors ) Regarding their use in the procedure. The present invention also relates to pharmaceutical compositions and formulations of the above combinations of tenofovir disoproxil fumarate and emtricitabine. Another aspect of the invention is a pharmaceutical formulation comprising a physiologically functional derivative of tenofovir disoproxil fumarate, or a physiologically functional derivative of emtricitabine.

The therapeutic combinations and pharmaceutical compositions and formulations of the present invention are PMEA compounds or PMPA (tenofovir) compounds and emtricitabine or (2R, 5S, cis) -4-amino-1- (2-hydroxymethyl-1,3). Includes the combination of -oxathiolan-5-yl)-(1H) -pyrimidin-2-one (3TC, lamivudine, Epivir ^TM ) and their use in the treatment of HIV infection.

One aspect of the invention is a method for the treatment or prevention of symptoms or effects of HIV infection in infected animals, which method is [2- (6-amino-purine-9-yl)-. 1-Methyl-ethoxymethyl] -phosphonate diisopropoxycarbonyloxymethyl ester fumarate (tenofovir DF, TDF) or its physiologically functional derivative, and (2R, 5S, cis) -4-amino-5- A combination of therapeutically effective amounts, including fluoro-1- (2-hydroxymethyl-1,3-oxathiolan-5-yl)-(1H) -pyrimidine-2-one (emtricitabine) or a physiologically functional derivative thereof. Is a method comprising the step of administering to this animal using (ie, the step of treating).

Another aspect of the invention is a unit dose form of a therapeutic combination comprising tenofovir disoproxil fumarate and emtricitabine, or physiologically functional derivatives thereof. This unit dosage form can be formulated for administration by the oral or other route and is unexpectedly chemically stable in light of the properties of the structurally diverse ingredients.

Another aspect of the invention relates to a chemically stable combination of antiviral compositions comprising tenofovir disoproxil fumarate and emtricitabine. In a further aspect of the invention, the chemically stable combination of tenofovir disoproxil fumarate and emtricitabine further comprises a third antiviral agent. In this three-component mixture, the unique chemical stability of tenofovir disoproxil fumarate and emtricitabine is utilized to allow combination with a third antiviral agent. Examples of particularly useful third agents include, but are not limited to, the agents in Table A. Preferably, the third component is an agent approved for antiviral use in humans, more preferably the third component is NNRTI or protease inhibitor (PI), and even more preferably. This third component is NNRTI. In a particularly preferred embodiment, the present invention relates to a combination of a chemically stable mixture of tenofovir disoproxil fumarate and emtricitabine with an efavilens.

Another aspect of the invention is the active ingredient and other antiviral agents selected from at least one, typically two, and optionally three, tenofovir disoproxil fumarate and emtricitabine, and fumar. A patient pack containing informational publications containing instructions on the use of tenofovir disoproxil acid and emtricitabine in combination.

の化合物を含む治療有効量の組成物を投与する工程を包含し、
ここで、Ｂは、アデニン、グアニン、シトシン、ウラシル、チミン、７−デアザアデニン、７−デアザグアニン、７−デアザ−８−アザグアニン、７−デアザ−８−アザアデニン、イノシン、ネブラリン、ニトロピロール、ニトロインドール、２−アミノプリン、２−アミノ−６−クロロプリン、２，６−ジアミノプリン、ヒポキサチン、シュードウリジン、５−フルオロシトシン、５−クロロシトシン、５−ブロモシトシン、５−ヨードシトシン、シュードシトシン、シュードイソシトシン、５−プロピニルシトシン、イソシトシン、イソグアニン、７−デアザグアニン、２−チオピリミジン、６−チオグアニン、４−チオチミン、４−チオウラシル、Ｏ^６−メチルグアニン、Ｎ^６−メチルアデニン、Ｏ^４−メチルチミン、５，６−ジヒドロチミン、５，６−ジヒドロウラシル、４−メチルインドール、およびピラゾロ［３，４−Ｄ］ピリミジンから選択され；そして
Ｒは、Ｈ、Ｃ_ｌ〜Ｃ_ｌ８アルキル、Ｃ_ｌ〜Ｃ_ｌ８置換アルキル、Ｃ_２〜Ｃ_ｌ８アルケニル、Ｃ_２〜Ｃ_ｌ８置換アルケニル、Ｃ_２〜Ｃ_ｌ８アルキニル、Ｃ_２〜Ｃ_ｌ８置換アルキニル、Ｃ_６〜Ｃ_２０アリール、Ｃ_６〜Ｃ_２０置換アリール、Ｃ_２〜Ｃ_２０複素環、Ｃ_２〜Ｃ_２０置換複素環、ホスホネート、ホスホホスホネート、ジホスホホスホネート、ホスフェート、ジホスフェート、トリホスフェート、ポリエチレンオキシ、およびプロドラッグ部分から選択される、
方法。
（項目９）
組成物の１つの成分が、（２Ｒ，５Ｓ，シス）−４−アミノ−１−（２−ヒドロキシメチル−１，３−オキサチオラン−５−イル）−（１Ｈ）−ピリミジン−２−オン（３ＴＣ）である、項目１に記載の方法。
（項目１０）
前記組成物が、鏡像異性体（２Ｒ，５Ｓ，シス）−４−アミノ−５−フルオロ−１−（２−ヒドロキシメチル−１，３−オキサチオラン−５−イル）−（１Ｈ）−ピリミジン−２−オンおよび（２Ｓ，５Ｒ，シス）−４−アミノ−５−フルオロ−１−（２−ヒドロキシメチル−１，３−オキサチオラン−５−イル）−（１Ｈ）−ピリミジン−２−オンのラセミ混合物である、エムトリシタビンの生理学的に機能的な誘導体を含む、項目１に記載の方法。
（項目１１）
項目１に記載の方法であって、前記組成物が、構造：

を有するフマル酸テノホビルジソプロキシルの生理学的に機能的な誘導体、またはその薬学的に受容可能な塩もしくはその溶媒和物を含み、
ここで、Ｒ^１およびＲ^２が、独立して、Ｈ、Ｃ_ｌ〜Ｃ_６アルキル、Ｃ_ｌ〜Ｃ_６置換アルキル、Ｃ_６〜Ｃ_２０アリール、Ｃ_６〜Ｃ_２０置換アリール、Ｃ_６〜Ｃ_２０アリールアルキル、Ｃ_６〜Ｃ_２０置換アリールアルキル、アシルオキシメチルエステル−ＣＨ_２ＯＣ（＝Ｏ）Ｒ、およびアシルオキシメチルカルボネート−ＣＨ_２ＯＣ（＝Ｏ）ＯＲ^９から選択され、ここでＲ^９が、Ｃ_ｌ〜Ｃ_６アルキル、Ｃ_ｌ〜Ｃ_６置換アルキル、Ｃ_６〜Ｃ_２０アリールおよびＣ_６〜Ｃ_２０置換アリールであり；
Ｒ^３が、Ｈ、Ｃ_ｌ〜Ｃ_６アルキル、Ｃ_ｌ〜Ｃ_６置換アルキル、またはＣＨ_２ＯＲ^８から選択され、ここでＲ^８が、Ｃ_ｌ〜Ｃ_６アルキル、Ｃ_ｌ〜Ｃ_６ヒドロキシアルキル、およびＣ_ｌ〜Ｃ_６ハロアルキルであり；
Ｒ^４およびＲ^５が、独立して、Ｈ、ＮＨ_２、ＮＨＲおよびＮＲ_２から選択され、ここでＲが、Ｃ_ｌ〜Ｃ_６アルキルであり；そして
Ｒ^６およびＲ^７が、独立して、ＨおよびＣ_ｌ〜Ｃ_６アルキルから選択される、
方法。
（項目１２）
Ｒ^１およびＲ^２のうちの少なくとも１つが、−ＣＨ_２ＯＣ（＝Ｏ）Ｃ（ＣＨ_３）_３である、項目１１に記載の方法。
（項目１３）
Ｒ^１およびＲ^２のうちの少なくとも１つが、−ＣＨ_２ＯＣ（＝Ｏ）ＯＣ（ＣＨ_３）_３である、項目１１に記載の方法。
（項目１４）
Ｒ^１およびＲ^２のうちの少なくとも１つが、−ＣＨ_２ＯＣ（＝Ｏ）ＯＣＨ（ＣＨ_３）_２である、項目１１に記載の方法。
（項目１５）
感染した動物におけるＨＩＶ感染症の症状または効果の処置または予防のための方法であって、治療有効量の［２−（６−アミノ−プリン−９−イル）−１−メチル−エトキシメチル］−ホスホン酸ジイソプロポキシカルボニルオキシメチルエステルフマレート（フマル酸テノホビルジソプロキシル）またはその生理学的に機能的な誘導体、および（２Ｒ，５Ｓ，シス）−４−アミノ−５−フルオロ−１−（２−ヒドロキシメチル−１，３−オキサチオラン−５−イル）−（１Ｈ）−ピリミジン−２−オン（エムトリシタビン）またはその生理学的に機能的な誘導体を組み合わせて投与するか、または交互に投与する工程を包含する、方法。
（項目１６）
フマル酸テノホビルジソプロキシルまたはその生理学的に機能的な誘導体、およびエムトリシタビンまたはその生理学的に機能的な誘導体が、交互に投与される、項目１５に記載の方法。
（項目１７）
フマル酸テノホビルジソプロキシルまたはその生理学的に機能的な誘導体、およびエムトリシタビンまたはその生理学的に機能的な誘導体が、単一組み合わせ処方物として組み合わされて投与される、項目１５に記載の方法。
（項目１８）
前記単一組み合わせ処方物が、１日あたり１回、感染したヒトに投与される、項目１７に記載の方法。
（項目１９）
前記動物がヒトである、項目１に記載の方法。
（項目２０）
前記組成物が、プロテアーゼインヒビター（ＰＩ）、ヌクレオシド逆転写酵素インヒビター（ＮＲＴＩ）、非ヌクレオシド逆転写酵素インヒビター（ＮＮＲＴＩ）、およびインテグラーゼインヒビターから選択される第３の活性成分をさらに含む、項目１に記載の方法。
（項目２１）
前記第３の活性成分が、９−［Ｒ−２−［［（Ｓ）−［［（Ｓ）−１−（イソプロポキシカルボニル）エチル］アミノ］−フェノキシホスフィニル］メトキシ］プロピル］アデニン（ＧＳ−７３４０）である、項目２０に記載の方法。
（項目２２）
前記組成物が、薬学的に受容可能な流動促進剤をさらに含む、項目１に記載の方法。
（項目２３）
前記流動促進剤が、二酸化ケイ素、粉末セルロース、微結晶性セルロース、ステアリン酸金属塩、アルミノケイ酸ナトリウム、安息香酸ナトリウム、炭酸カルシウム、ケイ酸カルシウム、コーンスターチ、炭酸マグネシウム、アスベストを含まない滑石、ステアロウェトＣ、デンプン、デンプン１５００、ラウリル硫酸マグネシウム、酸化マグネシウム、およびこれらの組み合わせから選択される、項目２２に記載の方法。
（項目２４）
前記ステアリン酸金属塩が、ステアリン酸カルシウム、ステアリン酸マグネシウム、ステアリン酸亜鉛、およびこれらの組み合わせから選択される、項目２３に記載の方法。
（項目２５）
［２−（６−アミノ−プリン−９−イル）−１−メチル−エトキシメチル］−ホスホン酸ジイソプロポキシカルボニルオキシメチルエステルフマレート（フマル酸テノホビルジソプロキシル）またはその生理学的に機能的な誘導体、および（２Ｒ，５Ｓ，シス）−４−アミノ−５−フルオロ−１−（２−ヒドロキシメチル−１，３−オキサチオラン−５−イル）−（１Ｈ）−ピリミジン−２−オン（エムトリシタビン）またはその生理学的に機能的な誘導体を含む、薬学的処方物。
（項目２６）
１つ以上の薬学的に受容可能なキャリアまたは賦形剤をさらに含む、項目２５に記載の薬学的処方物。
（項目２７）
前記薬学的に受容可能なキャリアまたは賦形剤が、糊化デンプン、クロスカルメロースナトリウム、ポビドン、ラクトース一水和物、微結晶性セルロース、およびステアリン酸マグネシウム；ならびにこれらの組み合わせから選択される、項目２６に記載の薬学的処方物。
（項目２８）
フマル酸テノホビルジソプロキシルまたはその生理学的に機能的な誘導体、およびエムトリシタビンまたはその生理学的に機能的な誘導体が、１：５０〜５０：１の重量比で存在する、項目２５に記載の薬学的処方物。
（項目２９）
テノホビルまたはその生理学的に機能的な誘導体、およびエムトリシタビンまたはその生理学的に機能的な誘導体が、１：１０〜１０：１の重量比で存在する、項目２５に記載の薬学的処方物。
（項目３０）
単位投与形態である、項目２５に記載の薬学的処方物。
（項目３１）
フマル酸テノホビルジソプロキシルまたはその生理学的に機能的な誘導体、およびエムトリシタビンまたはその生理学的に機能的な誘導体が、各々かつ個々に、単位投与形態１つあたり１００ｍｇ〜１０００ｍｇの量で存在する、項目３０に記載の薬学的処方物。
（項目３２）
フマル酸テノホビルジソプロキシルおよびエムトリシタビンを含む、項目３１に記載の薬学的処方物。
（項目３３）
約３００ｍｇのフマル酸テノホビルジソプロキシルおよび約２００ｍｇのエムトリシタビンを含む、項目３２に記載の薬学的処方物。
（項目３４）
経口投与に適切な、項目２５に記載の薬学的処方物。
（項目３５）
錠剤またはカプセル剤の形態である、項目２５に記載の薬学的処方物。
（項目３６）
感染したヒトへの１日あたり１回の投与に適切な、項目２５に記載の薬学的処方物。
（項目３７）
（２Ｒ，５Ｓ，シス）−４−アミノ−１−（２−ヒドロキシメチル−１，３−オキサチオラン−５−イル）−（１Ｈ）−ピリミジン−２−オン（３ＴＣ）であるエムトリシタビンの生理学的に機能的な誘導体を含む、項目２５に記載の薬学的処方物。
（項目３８）
項目２５に記載の薬学的処方物であって、前記組み合わせが、以下の構造：

を有するフマル酸テノホビルジソプロキシルの生理学的に機能的な誘導体、またはその薬学的に受容可能な塩もしくはその溶媒和物を含み、
ここで、Ｒ^１およびＲ^２が、独立して、Ｈ、Ｃ_ｌ〜Ｃ_６アルキル、Ｃ_ｌ〜Ｃ_６置換アルキル、Ｃ_６〜Ｃ_２０アリール、Ｃ_６〜Ｃ_２０置換アリール、Ｃ_６〜Ｃ_２０アリールアルキル、Ｃ_６〜Ｃ_２０置換アリールアルキル、アシルオキシメチルエステル−ＣＨ_２ＯＣ（＝Ｏ）Ｒ、およびアシルオキシメチルカルボネート−ＣＨ_２ＯＣ（＝Ｏ）ＯＲ^９から選択され、ここでＲ^９が、Ｃ_ｌ〜Ｃ_６アルキル、Ｃ_ｌ〜Ｃ_６置換アルキル、Ｃ_６〜Ｃ_２０アリールまたはＣ_６〜Ｃ_２０置換アリールであり；
Ｒ^３が、Ｈ、Ｃ_ｌ〜Ｃ_６アルキル、Ｃ_ｌ〜Ｃ_６置換アルキル、またはＣＨ_２ＯＲ^８であり、ここでＲ^８が、Ｃ_ｌ〜Ｃ_６アルキル、Ｃ_ｌ〜Ｃ_６ヒドロキシアルキル、またはＣ_ｌ〜Ｃ_６ハロアルキルであり；
Ｒ^４およびＲ^５が、独立して、Ｈ、ＮＨ_２、ＮＨＲおよびＮＲ_２から選択され、ここでＲが、Ｃ_ｌ〜Ｃ_６アルキルであり；そして
Ｒ^６およびＲ^７が、独立して、ＨおよびＣ_ｌ〜Ｃ_６アルキルから選択される、
薬学的処方物。
（項目３９）
Ｒ^１およびＲ^２のうちの少なくとも１つが、−ＣＨ_２ＯＣ（＝Ｏ）Ｃ（ＣＨ_３）_３である、項目３８に記載の薬学的処方物。
（項目４０）
Ｒ^１およびＲ^２のうちの少なくとも１つが、−ＣＨ_２ＯＣ（＝Ｏ）ＯＣ（ＣＨ_３）_３である、項目３８に記載の薬学的処方物。
（項目４１）
Ｒ^１およびＲ^２のうちの少なくとも１つが、−ＣＨ_２ＯＣ（＝Ｏ）ＯＣＨ（ＣＨ_３）_２である、項目３８に記載の薬学的処方物。
（項目４２）
［２−（６−アミノ−プリン−９−イル）−１−メチル−エトキシメチル］−ホスホン酸ジイソプロポキシカルボニルオキシメチルエステルフマレート（フマル酸テノホビルジソプロキシル）および（２Ｒ，５Ｓ，シス）−４−アミノ−５−フルオロ−１−（２−ヒドロキシメチル−１，３−オキサチオラン−５−イル）−（１Ｈ）−ピリミジン−２−オン（エムトリシタビン）から選択される少なくとも１つの活性成分、ならびにテノホビルおよびエムトリシタビンを一緒に組み合わせる使用に関する指示を含む情報掲載物を備える、患者用パック。
（項目４３）
１００ｍｇ〜１０００ｍｇのフマル酸テノホビルジソプロキシル、および１００ｍｇ〜１０００ｍｇのエムトリシタビンを共処方した、丸剤、錠剤、キャプレット、またはカプセル剤を備える、項目４２に記載の患者用パック。
（項目４４）
３００ｍｇのフマル酸テノホビルジソプロキシル、および２００ｍｇのエムトリシタビンを共処方した、丸剤、錠剤、キャプレット、またはカプセル剤を備える、項目４３に記載の患者用パック。
（項目４５）
１００ｍｇ〜１０００ｍｇのフマル酸テノホビルジソプロキシル、および１００ｍｇ〜１０００ｍｇのエムトリシタビンの別々の丸剤、錠剤、キャプレット、またはカプセル剤を備える、項目４２に記載の患者用パック。
（項目４６）
３００ｍｇのフマル酸テノホビルジソプロキシル、および２００ｍｇのエムトリシタビンの別々の丸剤、錠剤、キャプレット、またはカプセル剤を備える、項目４５に記載の患者用パック。
（項目４７）
フマル酸テノホビルジソプロキシルおよびエムトリシタビンの、化学的に安定な組み合わせ。
（項目４８）
前記組み合わせが、薬学的投与形態である、項目４７に記載の化学的に安定な組み合わせ。
（項目４９）
前記投与形態が、経口用である、項目４８に記載の化学的に安定な組み合わせ。
（項目５０）
第３の抗ウイルス剤をさらに含む、項目４７、項目４８、または項目４９のいずれか１項に記載の化学的に安定な組み合わせ。
（項目５１）
前記第３の抗ウイルス剤が、ＮＮＲＴＩまたはＰＩである、項目５０に記載の化学的に安定な組み合わせ。
（項目５２）
前記第３の抗ウイルス剤が、ＰＩである、項目５１に記載の化学的に安定な組み合わせ。
（項目５３）
前記第３の抗ウイルス剤が、ＮＮＲＴＩである、項目５１に記載の化学的に安定な組み合わせ。
（項目５４）
前記第３の抗ウイルス剤が、Ｒｅｙａｔａｚ、ＫａｌｅｔｒａまたはＳｕｓｔｉｖａから選択される、項目５０に記載の化学的に安定な組み合わせ。
（項目５５）
フマル酸テノホビルジソプロキシルおよびエムトリシタビンを含む、化学的に安定な経口用薬学的投与形態。
（項目５６）
フマル酸テノホビルジソプロキシル、エムトリシタビンおよびＲｅｙａｔａｚを含む、化学的に安定な経口用薬学的投与形態。
（項目５７）
フマル酸テノホビルジソプロキシル、エムトリシタビンおよびＫａｌｅｔｒａを含む、化学的に安定な経口用薬学的投与形態。
（項目５８）
フマル酸テノホビルジソプロキシル、エムトリシタビンおよびＳｕｓｔｉｖａを含む、化学的に安定な経口用薬学的投与形態。 Another aspect of the invention is the process for preparing the above combinations herein, which associates the combination tenofovir DF and emtricitabine in a pharmaceutical to provide an antiviral effect. Including the process. In a further aspect of the invention, the use of a combination of the invention in the manufacture of a medicament for the treatment of any of the above viral infections or conditions is provided.
The present invention provides, for example, the following aspects.
(Item 1)
A method for the treatment or prevention of symptoms or effects of HIV infection in an infected animal, wherein the animal is given [2- (6-amino-purine-9-yl) -1-methyl-ethoxymethyl]-. Phosphonate diisopropoxycarbonyloxymethyl ester fumarate (tenofovir disoproxil fumarate) or a physiologically functional derivative thereof, and (2R, 5S, cis) -4-amino-5-fluoro-1- (2) -Hydroxymethyl-1,3-oxathiolan-5-yl)-(1H) -pyrimidine-2-one (emtricitabine) or a physiologically functional derivative thereof to administer a therapeutically effective amount of the composition. Inclusive, method.
(Item 2)
The method of item 1, wherein the composition comprises tenofovir disoproxil fumarate and emtricitabine.
(Item 3)
The method of item 2, wherein the composition comprises about 300 mg of tenofovir disoproxil fumarate and about 200 mg of emtricitabine.
(Item 4)
The first item, wherein tenofovir disoproxil fumarate or a physiologically functional derivative thereof and emtricitabine or a physiologically functional derivative thereof are present in a weight ratio of about 1:50 to about 50: 1. Method.
(Item 5)
The first item, wherein tenofovir disoproxil fumarate or a physiologically functional derivative thereof and emtricitabine or a physiologically functional derivative thereof are present in a weight ratio of about 1: 10 to about 10: 1. Method.
(Item 6)
Item 1 in which tenofovir disoproxil fumarate or a physiologically functional derivative thereof and emtricitabine or a physiologically functional derivative thereof are present in an amount of about 1 mg to about 1000 mg per unit dosage form, respectively. The method described.
(Item 7)
Item 1 in which tenofovir disoproxil fumarate or a physiologically functional derivative thereof and emtricitabine or a physiologically functional derivative thereof are present in an amount of about 100 mg to about 300 mg per unit dosage form, respectively. The method described.
(Item 8)
A method for the treatment or prevention of symptoms or effects of HIV infection in an infected animal, wherein the animal is given [2- (6-amino-purine-9-yl) -1-methyl-ethoxymethyl]-. Phosphonate diisopropoxycarbonyloxymethyl ester fumarate (tenofovir disoproxil fumarate) or its physiologically functional derivative, and formula:

Including the step of administering a therapeutically effective amount of the composition containing the compound of
Here, B is adenine, guanine, cytosine, uracil, timidine, 7-deazaadenine, 7-deazaguanin, 7-deaza-8-azaguanine, 7-deaza-8-azaadenine, cytosine, nebulin, nitropyrrole, nitroindole, 2-aminopurine, 2-amino-6-chloropurine, 2,6-diaminopurine, hypoxatin, pseudouridine, 5-fluorocytosine, 5-chlorocytosine, 5-bromocytosine, 5-iodocytosine, pseudocytosine, pseudo isocytosine, 5-propynyl cytosine, isocytosine, isoguanine, 7-deazaguanine, 2-thiopyrimidine, 6-thioguanine, 4-thiothymine, 4-thiouracil, ^{O 6} - methylguanine, ^{N 6} - methyl adenine, ^{O 4} - methylthymine, Selected from 5,6-dihydrotimine, 5,6-dihydrouracil, 4-methylindole, and pyrazolo [3,4-D] pyrimidines; and R is H, C _{l to} C _l8 alkyl, C _l to C. _l8 substituted _alkyl, C 2 _{-C l8 alkenyl,} C 2 _{-C l8} substituted _alkenyl, C 2 _{-C l8 alkynyl,} C 2 _{-C l8} substituted _alkynyl, C 6 _{-C 20 aryl,} C 6 _{-C 20} substituted aryl, C Selected from _{2 to} C ₂₀ heterocycles, C _{2 to} C ₂₀ substituted heterocycles, phosphonates, phosphophosphonates, diphosphophosphonates, phosphates, diphosphates, triphosphates, polyethyleneoxy, and prodrug moieties.
Method.
(Item 9)
One component of the composition is (2R, 5S, cis) -4-amino-1- (2-hydroxymethyl-1,3-oxathiolan-5-yl)-(1H) -pyrimidine-2-one (3TC). ), The method according to item 1.
(Item 10)
The composition is an enantiomer (2R, 5S, cis) -4-amino-5-fluoro-1- (2-hydroxymethyl-1,3-oxathiolane-5-yl)-(1H) -pyrimidine-2. Racemic mixture of -one and (2S, 5R, cis) -4-amino-5-fluoro-1- (2-hydroxymethyl-1,3-oxathiolan-5-yl)-(1H) -pyrimidine-2-one The method of item 1, wherein the method comprises a physiologically functional derivative of emtricitabine.
(Item 11)
The method according to item 1, wherein the composition has a structure:

Contains a physiologically functional derivative of tenofovir disoproxil fumarate, or a pharmaceutically acceptable salt thereof or a solvate thereof.
Here, R ¹ and R ² are independently H, C _{l to} C ₆ alkyl, C _{l to} C ₆ substituted alkyl, C _{6 to} C ₂₀ aryl, C _{6 to} C ₂₀ substituted aryl, C ₆ to C. ₂₀ arylalkyl, C _{6 to} C _20- substituted arylalkyl, acyloxymethyl ester-CH ₂ OC (= O) R, and acyloxymethyl carbonate-CH ₂ OC (= O) OR ^{9 are} selected, where R ⁹ is , C _{l to} C ₆ alkyl, C _{l to} C ₆ substituted alkyl, C _{6 to} C ₂₀ aryl and C _{6 to} C ₂₀ substituted aryl;
R ³ is selected from H, C _{l to} C ₆ alkyl, C _{l to} C ₆ substituted alkyl, or CH ₂ OR ⁸ , where R ⁸ is C _{l to} C ₆ alkyl, C _{l to} C ₆ hydroxyalkyl. , And C _{l to} C ₆ haloalkyl;
R ⁴ and R ⁵ are independently selected from H, NH ₂ , NHR and NR ₂ , where R is _{Cl to} C ₆ alkyl; and R ⁶ and R ⁷ are independent. Selected from H and C _{l to} C ₆ alkyl,
Method.
(Item 12)
The method of item 11, wherein at least one of R ¹ and R ² is -CH ₂ OC (= O) C (CH ₃ ) ₃ .
(Item 13)
The method of item 11, wherein at least one of R ¹ and R ² is −CH ₂ OC (= O) OC (CH ₃ ) ₃ .
(Item 14)
The method of item 11, wherein at least one of R ¹ and R ² is -CH ₂ OC (= O) OCH (CH ₃ ) ₂ .
(Item 15)
A method for the treatment or prevention of symptoms or effects of HIV infection in infected animals, with therapeutically effective amounts of [2- (6-amino-purine-9-yl) -1-methyl-ethoxymethyl]-. Phosphonate diisopropoxycarbonyloxymethyl ester fumarate (tenofovir disoproxil fumarate) or a physiologically functional derivative thereof, and (2R, 5S, cis) -4-amino-5-fluoro-1- (2) -Hydroxymethyl-1,3-oxathiolan-5-yl)-(1H) -pyrimidine-2-one (emtricitabine) or a physiologically functional derivative thereof is administered in combination or alternately. Inclusive, method.
(Item 16)
15. The method of item 15, wherein tenofovir disoproxil fumarate or a physiologically functional derivative thereof and emtricitabine or a physiologically functional derivative thereof are administered alternately.
(Item 17)
15. The method of item 15, wherein tenofovir disoproxil fumarate or a physiologically functional derivative thereof and emtricitabine or a physiologically functional derivative thereof are administered in combination as a single combination formulation.
(Item 18)
17. The method of item 17, wherein the single combination formulation is administered to an infected human once per day.
(Item 19)
The method of item 1, wherein the animal is a human.
(Item 20)
Item 1 wherein the composition further comprises a third active ingredient selected from a protease inhibitor (PI), a nucleoside reverse transcriptase inhibitor (NRTI), a non-nucleoside reverse transcriptase inhibitor (NNRTI), and an integrase inhibitor. The method described.
(Item 21)
The third active ingredient is 9- [R-2-[[(S)-[[(S) -1- (isopropoxycarbonyl) ethyl] amino] -phenoxyphosphinyl] methoxy] propyl] adenine ( GS-7340), the method of item 20.
(Item 22)
The method of item 1, wherein the composition further comprises a pharmaceutically acceptable flow enhancer.
(Item 23)
The flow accelerator is silicon dioxide, powdered cellulose, microcrystalline cellulose, metal stearate, sodium aluminosilicate, sodium benzoate, calcium carbonate, calcium silicate, corn starch, magnesium carbonate, asbestos-free talc, stearowet C. , Starch, Starch 1500, Magnesium Lauryl Sulfate, Magnesium Oxide, and Combinations thereof, item 22.
(Item 24)
23. The method of item 23, wherein the metal stearate salt is selected from calcium stearate, magnesium stearate, zinc stearate, and combinations thereof.
(Item 25)
[2- (6-amino-purine-9-yl) -1-methyl-ethoxymethyl] -phosphonate diisopropoxycarbonyloxymethyl ester fumarate (tenofovir disoproxil fumarate) or its physiologically functional Derivatives and (2R, 5S, cis) -4-amino-5-fluoro-1- (2-hydroxymethyl-1,3-oxathiolan-5-yl)-(1H) -pyrimidine-2-one (emtricitabine) Or a pharmaceutical formulation comprising a physiologically functional derivative thereof.
(Item 26)
25. The pharmaceutical formulation according to item 25, further comprising one or more pharmaceutically acceptable carriers or excipients.
(Item 27)
The pharmaceutically acceptable carrier or excipient is selected from gelatinized starch, croscarmellose sodium, povidone, lactose monohydrate, microcrystalline cellulose, and magnesium stearate; and combinations thereof. 26. The pharmaceutical formulation according to item 26.
(Item 28)
25. The pharmaceutical formula according to item 25, wherein tenofovir disoproxil fumarate or a physiologically functional derivative thereof and emtricitabine or a physiologically functional derivative thereof are present in a weight ratio of 1:50 to 50: 1. Prescription.
(Item 29)
25. The pharmaceutical formulation according to item 25, wherein tenofovir or a physiologically functional derivative thereof and emtricitabine or a physiologically functional derivative thereof are present in a weight ratio of 1:10 to 10: 1.
(Item 30)
25. The pharmaceutical formulation according to item 25, which is a unit dosage form.
(Item 31)
An item in which tenofovir disoproxil fumarate or a physiologically functional derivative thereof and emtricitabine or a physiologically functional derivative thereof are present individually and individually in an amount of 100 mg to 1000 mg per unit dosage form. 30. The pharmaceutical formulation.
(Item 32)
31. The pharmaceutical formulation according to item 31, which comprises tenofovir disoproxil fumarate and emtricitabine.
(Item 33)
32. The pharmaceutical formulation of item 32, comprising about 300 mg of tenofovir disoproxil fumarate and about 200 mg of emtricitabine.
(Item 34)
25. The pharmaceutical formulation suitable for oral administration.
(Item 35)
25. The pharmaceutical formulation according to item 25, which is in the form of tablets or capsules.
(Item 36)
25. The pharmaceutical formulation of item 25, suitable for once-daily administration to infected humans.
(Item 37)
Physiologically of emtricitabine (2R, 5S, cis) -4-amino-1- (2-hydroxymethyl-1,3-oxathiolan-5-yl)-(1H) -pyrimidine-2-one (3TC) 25. The pharmaceutical formulation according to item 25, comprising a functional derivative.
(Item 38)
25. The pharmaceutical formulation according to item 25, wherein the combination has the following structure:

Contains a physiologically functional derivative of tenofovir disoproxil fumarate, or a pharmaceutically acceptable salt thereof or a solvate thereof.
Here, R ¹ and R ² are independently H, C _{l to} C ₆ alkyl, C _{l to} C ₆ substituted alkyl, C _{6 to} C ₂₀ aryl, C _{6 to} C ₂₀ substituted aryl, C ₆ to C. ₂₀ arylalkyl, C _{6 to} C _20- substituted arylalkyl, acyloxymethyl ester-CH ₂ OC (= O) R, and acyloxymethyl carbonate-CH ₂ OC (= O) OR ^{9 are} selected, where R ⁹ is , C _{l to} C ₆ alkyl, C _{l to} C _6- substituted alkyl, C _{6 to} C ₂₀ aryl or C _{6 to} C _20- substituted aryl;
R ³ is H, C _{l to} C ₆ alkyl, C _{l to} C ₆ substituted alkyl, or CH ₂ OR ⁸ , where R ⁸ is C _{l to} C ₆ alkyl, C _{l to} C ₆ hydroxyalkyl, Or C _{l to} C ₆ haloalkyl;
R ⁴ and R ⁵ are independently selected from H, NH ₂ , NHR and NR ₂ , where R is _{Cl to} C ₆ alkyl; and R ⁶ and R ⁷ are independent. Selected from H and C _{l to} C ₆ alkyl,
Pharmaceutical prescription.
(Item 39)
38. The pharmaceutical formulation according to item 38, wherein at least one of R ¹ and R ² is -CH ₂ OC (= O) C (CH ₃ ) ₃ .
(Item 40)
38. The pharmaceutical formulation according to item 38, wherein at least one of R ¹ and R ² is -CH ₂ OC (= O) OC (CH ₃ ) ₃ .
(Item 41)
38. The pharmaceutical formulation according to item 38, wherein at least one of R ¹ and R ² is -CH ₂ OC (= O) OCH (CH ₃ ) ₂ .
(Item 42)
[2- (6-amino-purine-9-yl) -1-methyl-ethoxymethyl] -phosphonate diisopropoxycarbonyloxymethyl ester fumarate (tenofovir disoproxil fumarate) and (2R, 5S, cis) At least one active ingredient selected from -4-amino-5-fluoro-1- (2-hydroxymethyl-1,3-oxathiolan-5-yl)-(1H) -pyrimidine-2-one (emtricitabine), A patient pack that also contains informational publications containing instructions on the use of tenofovir and emtricitabine combined together.
(Item 43)
42. The patient pack of item 42, comprising pills, tablets, caplets, or capsules co-prescribed with 100 mg to 1000 mg tenofovir disoproxil fumarate and 100 mg to 1000 mg emtricitabine.
(Item 44)
43. The patient pack of item 43, comprising a pill, tablet, caplet, or capsule co-prescribed with 300 mg tenofovir disoproxil fumarate and 200 mg emtricitabine.
(Item 45)
42. The patient pack of item 42, comprising 100 mg to 1000 mg of tenofovir disoproxil fumarate and 100 mg to 1000 mg of emtricitabine in separate pills, tablets, caplets, or capsules.
(Item 46)
45. The patient pack of item 45, comprising 300 mg of tenofovir disoproxil fumarate and 200 mg of emtricitabine in separate pills, tablets, caplets, or capsules.
(Item 47)
A chemically stable combination of tenofovir disoproxil fumarate and emtricitabine.
(Item 48)
The chemically stable combination according to item 47, wherein the combination is a pharmaceutical dosage form.
(Item 49)
The chemically stable combination according to item 48, wherein the dosage form is for oral use.
(Item 50)
The chemically stable combination according to any one of items 47, 48, or 49, further comprising a third antiviral agent.
(Item 51)
The chemically stable combination according to item 50, wherein the third antiviral agent is NNRTI or PI.
(Item 52)
The chemically stable combination according to item 51, wherein the third antiviral agent is PI.
(Item 53)
The chemically stable combination according to item 51, wherein the third antiviral agent is NNRTI.
(Item 54)
The chemically stable combination of item 50, wherein the third antiviral agent is selected from Reyataz, Kaletra or Sustiva.
(Item 55)
A chemically stable oral pharmaceutical dosage form comprising tenofovir disoproxil fumarate and emtricitabine.
(Item 56)
A chemically stable oral pharmaceutical dosage form comprising tenofovir disoproxil fumarate, emtricitabine and Reyataz.
(Item 57)
A chemically stable oral pharmaceutical dosage form comprising tenofovir disoproxil fumarate, emtricitabine and Kaletra.
(Item 58)
A chemically stable oral pharmaceutical dosage form comprising tenofovir disoproxil fumarate, emtricitabine and Sustiva.

(Detailed description of the invention)
Although the present invention is described with the listed claims, it is understood that the present invention is not intended to limit the present invention to this claim. In contrast, the invention is intended to cover all alternatives, modifications, and equivalents that may be included within the scope of the invention as defined by the claims.

(Definition)
Unless otherwise stated, the following terms and phrases are intended to have the following meanings as used herein:
When the trade name is used herein, the applicant intends to independently include the product of this trade name and the active pharmaceutical ingredient of the product of this trade name.

The term "chemical stability" means that the two major antiviral agents combined are substantially stable to chemical degradation. Preferably, they are sufficiently stable in physical combinations that allow a commercially useful shelf life of the combination product. Typically, "chemically stable" means that when the two components are physically combined to form a pharmaceutical dosage form, the first component of this mixture decomposes the second component. It means that it does not work like that. More typically, "chemically stable" means that the acidity of the first component does not catalyze or otherwise accelerate the acid decomposition of the second component. By way of example, but not limited to, in one aspect of the invention, "chemically stable" means that tenofovir disoproxil fumarate is substantially not degraded by the acidity of emtricitabine. "Substantially" in this context means at least less than about 10%, preferably less than 1%, more preferably 0.1, over a 24-hour period when the product is present in a pharmaceutical dosage form. It means the acid degradation of less than%, even more preferably less than 0.01% tenofovir disoproxil fumarate.

The terms "synergistic" and "synergistic" mean that the effect achieved with the compounds used together is greater than the sum of the effects produced by using the compounds separately (ie, administered separately). It means that the effect is larger than the expected effect based on the two active ingredients. The synergistic effect is whether the compounds are: (1) co-prescribed and administered, or delivered simultaneously in a combined formulation; (2) delivered alternately or in parallel as separate formulations. Or (3) can be obtained if administered by some other regimen. When delivered in alternating treatments, the synergistic effect is when the compounds are sequentially administered or delivered, for example, in separate tablets, pills or capsules, or by separate infusions in separate syringes. , Can be acquired. Generally, during alternating treatments, each active ingredient in an effective dose is administered sequentially (ie, sequentially), while in combination therapy, two or more active ingredients in an effective dose are together. Be administered. The synergistic antiviral effect exhibits greater antiviral effect than the expected purely additive effect of the individual compounds in the combination.

The term "physiologically functional derivative" is the physiological function equivalent to or close to that of tenofovir DF or emtricitabine when administered in combination with another pharmaceutically active compound in the combination of the invention. It means a pharmaceutically active compound having a physiological function. As used herein, the term "physiologically functional derivative" is any of the following: physiologically acceptable salts, ethers, esters, prodrugs, mixtures, racemates (enantiomers). Such compounds or antiviralally active metabolites or residues thereof upon administration to the body, diastereomers, or stereoisomer-rich mixtures or racemic mixtures () and recipients (including residues). Includes any other compound that can be provided, either directly or indirectly.

"Bioavailability" is the degree to which a pharmaceutically active drug becomes available to a target tissue after introduction of the drug into the body. Increased bioavailability of pharmaceutically active drugs may provide more effective and effective treatments for patients. This is because, for a given dose, more pharmaceutically active agents are effective at the target tissue site.

The compounds of the combination of the present invention can be referred to as "active ingredients" or "pharmaceutically active agents".

As used herein, the term "prodrug" refers to a drug substrate (ie, as a result of naturally occurring chemical reactions, enzyme-catalyzed chemical reactions, and / or metabolic chemical reactions when administered to a biological system. , Active ingredient).

"Prodrug moiety" means an unstable functional group that separates from an activity-inhibiting compound during metabolism, systemically, intracellularly, by hydrolysis, enzymatic cleavage, or by some other process. (Editbook of Drug Design and Development (1991), Bundgaard, Hands, "Design and Application of Prodrugs", P. Krogsgaard-Bard-Lars, ed. The prodrug moiety may help increase solubility, absorption, and lipophilicity, optimizing drug delivery, bioavailability, and efficacy. Thus, a "prodrug" is a covalently modified analog of a therapeutically active compound.

An "alkyl" is a saturated or unsaturated, branched, linear chain derived by the removal of a single hydrogen atom from a single carbon atom of the original alkane, alkene, or alkyne. , Branched chain or cyclic hydrocarbon group. A typical alkyl group consists of 1 to 18 saturated carbons and / or unsaturated carbons (eg, linear carbon atoms, secondary carbon atoms, tertiary carbon atoms or cyclic carbon atoms). Examples include, but are not limited to: methyl, Me (-CH ₃ ), ethyl, Et (-CH ₂ CH ₃ ), acetylene (-C ≡ CH), ethylene, vinyl (-CH =). CH ₂ ), 1-propyl, n-Pr, n-propyl (-CH ₂ CH ₂ CH ₃ ), 2-propyl, i-Pr, i-propyl (-CH (CH ₃ ) ₂ ), allyl (-CH) ₂ CH = CH ₂ ), propargyl (-CH ₂ C ≡ CH), cyclopropyl (-C ₃ H ₅ ), 1-butyl, n-Bu, n-butyl (-CH ₂ CH ₂ CH ₂ CH ₃ ), 2-Methyl-1-propyl, i-Bu, i-Butyl (-CH ₂ CH (CH ₃ ) ₂ ), 2-Butyl, s-Bu, s-Butyl (-CH (CH ₃ ) CH ₂ CH ₃ ) , 2-Methyl-2-propyl, t-Bu, t-Butyl (-C (CH ₃ ) ₃ ), 1-Pentyl, n-Pentyl, (-CH ₂ CH ₂ CH ₂ CH ₂ CH ₃ ), 2- Pentil (-CH (CH ₃ ) CH ₂ CH ₂ CH ₃ ), 3-Pentyl (-CH (CH ₂ CH ₃ ) ₂ ), 2-Methyl-2-butyl (-C (CH ₃ ) ₂ CH ₂ CH ₃ ) ), Cyclopropyl (-C ₅ H ₉ ), 3-Methyl-2-butyl (-CH (CH ₃ ) CH (CH ₃ ) ₂ ), 3-Methyl-1-butyl (-CH ₂ CH ₂ CH (CH)) ₃ ) ₂ ), 2-Methyl-1-butyl (-CH ₂ CH (CH ₃ ) CH ₂ CH ₃ ), 1-hexyl (-CH ₂ CH ₂ CH ₂ CH ₂ CH ₂ CH ₃ ), 5-hexenyl (-CH ₂ CH ₂ CH ₂ CH ₂ CH ₂ CH ₃ ) -CH ₂ CH ₂ CH ₂ CH ₂ CH = CH ₂ ) 1-hexyl (-CH (CH ₃ ) CH ₂ CH ₂ CH ₂ CH ₃ ), 3-hexyl (-CH (CH ₂ CH ₃ ) (CH ₂ CH) ₂ CH ₃ )), cyclohexyl (-C ₆ H ₁₁ ), 2-methyl-2-pentyl (-C (CH ₃ ) ₂ CH ₂ CH ₂ CH ₃ ), 3-methyl-2-pentyl (-CH (CH)) ₃ ) CH (CH ₃ ) CH ₂ CH ₃ ), 4-methyl-2-pentyl (-CH (CH ₃ ) CH ₂ CH (CH ₃ ) ₂ ), 3-methyl-3-pentyl (-C (CH ₃ )) ) (CH ₂ CH ₃ ) ₂ ) , 2-Methyl-3-pentyl (-CH (CH ₂ CH ₃ ) CH (CH ₃ ) ₂ ), 2,3-Dimethyl-2-butyl (-C (CH ₃ ) ₂ CH (CH ₃ ) ₂ ), And 3,3-dimethyl-2-butyl (-CH (CH ₃ ) C (CH ₃ ) ₃ ).

"Aryl" means a monovalent aromatic hydrocarbon group of 6 to 20 carbon atoms derived by the removal of one hydrogen atom from a single carbon atom in the original aromatic ring system. .. Typical aryl groups include, but are not limited to, groups derived from benzene, substituted benzene, naphthalene, anthracene, biphenyl and the like.

"Arylalkyl" (typically a terminal carbon atom or sp ³ carbon atoms) carbon atoms one of hydrogen atoms bonded to, is substituted with an aryl group, refers to an acyclic alkyl group. Typical arylalkyl groups include benzyl, 2-phenylethane-1-yl, 2-phenylethane-1-yl, naphthylmethyl, 2-naphthylethane-1-yl, 2-naphthylethane-1-yl and naphtho. Benzyl, 2-naphthophenylethane-1-yl and the like can be mentioned, but the present invention is not limited thereto. The 6 to 20 carbon atoms of an arylalkyl group are, for example, the alkyl moiety of an arylalkyl group (including an alkenyl group, alkenyl group or alkynyl group) is 1 to 6 carbon atoms, and the aryl moiety is 5. ~ 14 carbon atoms.

"Substituent alkyl", "substituted aryl", and "substituted arylalkyl" mean alkyl, aryl, and arylalkyl in which one or more hydrogen atoms are each independently substituted with a substituent. Exemplary substituents include but are not limited ^{to: -X, -R, -O -,} -OR, -SR, -S -, -NR 2, -NR 3, = NR, -CX ₃ , -CN, -OCN, -SCN, -N = C = O, -NCS, -NO, -NO ₂ , = N ₂ , -N ₃ , NC (= O) R, -C (= O) ^{_{) R, -C (= O)}} NRR, -S (= O) 2 O -, -S (= O) 2 OH, -S (= O) 2 R, -OS (= O) 2 OR, -S _{(= O) 2 NR, -S} (= O) R, -OP (= O) O 2 RR, -P (= O) O 2 RR-P (= O) (O -) 2, -P (= _{O) (OH) 2, -C} (= O) R, -C (= O) X, -C (S) R, -C (O) OR, -C (O) O -, -C (S) OR, -C (O) SR, -C (S) SR, -C (O) NRR, -C (S) NRR, -C (NR) NRR. Here, each X is independently a halogen (F, Cl, Br, or I); and each R is independently a -H, alkyl, aryl, heterocycle, or prodrug moiety.

"Heteroaryl" and "heterocycle" refer to a ring system in which one or more ring atoms are heteroatoms (eg, nitrogen, oxygen and sulfur). Heterocycles are described below: Katritzky, Alan R. Katritzky, Alan R. , Rees, C.I. W. , And Scriven, E. et al. Heterocyclic Chemistry (1996) Pergamon Press; Paquette, Leo A. et al. Principles of Modern Heterocyclic Chemistry W. et al. A. Benjamin, New York, (1968), especially Chapter 1, Chapter 3, Chapter 4, Chapter 6, Chapter 7, and Chapter 9; "The Chemistry of Heterocyclic Compounds, Aseries of Monographs" (Jones of Monographs).
Wiley & Sons, New York, from 1950 to the present), especially Volumes 13, 14, 16, 19, 19, and 28. Exemplary heterocycles include, but are not limited to, the following substituents: pyrazole, indol, furan, benzofuran, thiophene, benzothiophene, 2-pyridyl, 3-pyridyl, 4-pyridyl, -Kinolyl, 3-quinolyl, 4-quinolyl, 2-imidazole, 4-imidazole, 3-pyrazole, 4-pyrazole, pyridazine, pyrimidine, pyrazine, purine, synolin, phthalazine, quinazoline, quinoxalin, 3- (1,2,2, 4-N) -triazolyl, 5- (1,2,4-N) -triazolyl, 5-tetrazolyl, 4- (1-O,3-N) -oxazole, 5- (1-O,3-N) -Oxazole, 4- (1-S, 3-N) -thiazole, 5- (1-S, 3-N) -thiazole, 2-benzoxazole, 2-benzothiazole, 4- (1,2,3) -N) -Groups derived from benzotriazole and benzimidazole.

The definitions and conventions of stereochemistry used herein are generally S.I. P. Parker ed., McGraw-Hill Dictionary of Chemical Terms (1984) McGraw-Hill Book Company, New York; and Eliel, E. et al. And Wilen, S. et al. , Stereochemistry of Organic Compounds (1994) John Wiley & Sons, Inc. , Follow New York. Many organic compounds exist in optically active form. That is, they have the ability to rotate plane-polarized planes. In describing optically active compounds, the prefixes D and L, or R and S, are used to represent the absolute configuration of the molecule around its chiral center. The prefixes d and l, or (+) and (-), are used to represent the sign of the rotation of plane polarized light by the compound. (-) Or L means that the compound is dextrorotatory. Compounds prefixed with (+) or d are dextrorotatory. For a given chemical structure, these compounds, called stereoisomers, are identical except that they are mirror images of each other. Certain stereoisomers are also referred to as enantiomers, and mixtures of such isomers are often referred to as enantiomer mixtures. A 50:50 mixture of enantiomers is referred to as a racemic mixture or racemic compound. The terms "racemic mixture" and "racemic compound" refer to an equimolar mixture of two enantiomeric species (lacking optical activity).

The term "chiral" refers to a molecule having properties that cannot be superimposed on a mirror image partner, while the term "achiral" refers to a molecule that can be superimposed on those mirror image partners.

The term "terometric isomer" refers to a compound having the same chemical composition but different in terms of the arrangement of atoms or groups in space.

"Diastereomer" refers to a stereoisomer having two or more chirality centers and these molecules are not mirror images of each other. Diastereomers have different physical properties (eg, melting point, boiling point, spectral properties, and reactivity). Mixtures of diastereomers can be separated based on high resolution analytical procedures (eg, electrophoresis and chromatography).

"Enantiomers" refer to two stereoisomers of compounds that are mirror images that cannot be superimposed on each other.

(Combination active ingredient)
The present invention provides a novel combination of two or more active ingredients used together. In some embodiments, synergistic antiviral effects are achieved. In other embodiments, chemically stable combinations are obtained. This combination comprises (1) at least one active ingredient selected from tenofovir disoproxil fumarate and physiologically functional derivatives, and (2) at least one selected from emtricitabine and physiologically functional derivatives. Contains one active ingredient. The term "synergistic antiviral effect" is used herein to represent an antiviral effect greater than the expected purely additive effect of the individual components (a) and (b) of the combination. To.

Also known as tenofovir disoprodrug (Vired®, tenofovir DF, tenofovir disoprodrug, TDF, bis-POC-PMPA (US Patents 5935946, 5922695, 5977089, 6043230). , No. 6069249)) is a prodrug of tenofovir, and has the following structure:

を有し、そしてフマル酸塩（ＨＯ_２ＣＣＨ_２ＣＨ_２ＣＯ_２ ⁻）を含む。

Have, and fumarate ^- containing _{(HO 2 CCH 2 CH 2 CO} 2).

Chemical names for tenofobil disoproxil fumarate include: [2- (6-amino-purine-9-yl) -1-methyl-ethoxymethyl] -phosphonate diisopropoxycarbonyloxymethyl ester 9-[(R) -2-[[Bis [[(isopropoxycarbonyl) oxy] methoxy] phosphinyl] methoxy] propyl] adenine; and 2,4,6,8-tetraoxa-5-phosfanonanesionic acid , 5-[[(1R) -2- (6-amino-9H-purine-9-yl) -1-methylethoxy] methyl-, bis (1-methylethyl) ester, 5-oxide. CAS Registry Numbers include: 201341-05-1; 202138-50-9; 206184-49-8. It should be noted that the ethoxymethyl unit of tenofovir has a chiral center. The R (right (rectus), clockwise configuration) enantiomer is shown. However, the present invention also includes the S isomer. The present invention includes all enantiomers, diastereomers, racemic compounds, and stereoisomer-rich mixtures of tenofovir (PMPA), as well as physiologically functional derivatives thereof.

PMPA or tenofovir (US Pat. Nos. 4808716, 5733788, 6057305) has the following structure:

を有する。

Have.

Chemical names for PMPA, tenofovir include: (R) -9- (2-phosphonylmethoxypropyl) adenine; and phosphonic acid, [[(1R) -2- (6-amino-9H-purine). -9-yl) -1-methylethoxy] methyl]. The CAS Registry Number is 147127-20-6.

Tenofovir disoproxil fumarate (DF) is a nucleotide reverse transcriptase inhibitor approved in the United States in 2001 for the treatment of HIV-1 infection in combination with other antiretroviral agents. Tenofovir disoproxil fumarate or Viread® (Gilead Science, Inc.) is a fumarate of tenofovir disoproxil. Viread® may be named as follows: 9-[(R) -2-[[bis [[(isopropoxycarbonyl) oxy] methoxy] phosphinyl] methoxy] propyl] adenine fumarate (1). 1); or 2,4,6,8-tetraoxa-5-phosfanona nejionic acid, 5-[[(1R) -2- (6-amino-9H-purine-9-yl) -1-methyl) Ethoxy] methyl]-, bis (1-methylethyl) ester, 5-oxide, (2E) -2-buteneionate (1: 1). The CAS Registry Number is 202138-50-9.

Physiologically functional derivatives of tenofovir disoproxil fumarate include PMEA (adehovir, 9-((R) -2- (phosphonomethoxy) ethyl) adenine), and PMPA compounds. Illustrative combinations include PMEA or PMPA compounds in combination with emtricitabine or 3TC. The PMEA compound and PMPA compound have the following structures:

を有し、
ここで、ＰＭＥＡについては、Ｒ^３はＨであり、そしてＰＭＰＡについては、Ｒ^３は、Ｃ_１〜Ｃ_６アルキル、Ｃ_１〜Ｃ_６置換アルキル、またはＣＨ_２ＯＲ^８であり、ここでＲ^８は、Ｃ_１〜Ｃ_６アルキル、Ｃ_１〜Ｃ_６ヒドロキシアルキル、またはＣ_１〜Ｃ_６ハロアルキルである。Ｒ^６およびＲ^７は、独立して、ＨまたはＣ_１〜Ｃ_６アルキルである。Ｒ^４およびＲ^５は、独立して、Ｈ、ＮＨ_２、ＮＨＲまたはＮＲ_２であり、ここでＲは、Ｃ_１〜Ｃ_６アルキルである。Ｒ^１およびＲ^２は、独立して、Ｈ、Ｃ_ｌ〜Ｃ_６アルキル、Ｃ_ｌ〜Ｃ_６置換アルキル、Ｃ_６〜Ｃ_２０アリール、Ｃ_６〜Ｃ_２０置換アリール、Ｃ_６〜Ｃ_２０アリールアルキル、Ｃ_６〜Ｃ_２０置換アリールアルキル、アシルオキシメチルエステル−ＣＨ_２ＯＣ（＝Ｏ）Ｒ^９（例えば、ＰＯＭ）、またはアシルオキシメチルカルボネート−ＣＨ_２ＯＣ（＝Ｏ）ＯＲ^９（例えば、ＰＯＣ）であり、ここでＲ^９は、Ｃ_ｌ〜Ｃ_６アルキル、Ｃ_ｌ〜Ｃ_６置換アルキル、Ｃ_６〜Ｃ_２０アリールまたはＣ_６〜Ｃ_２０置換アリールである。例えば、Ｒ^１およびＲ^２は、ピバロイルオキシメトキシ、ＰＯＭ、−ＣＨ_２ＯＣ（＝Ｏ）Ｃ（ＣＨ_３）_３；−ＣＨ_２ＯＣ（＝Ｏ）ＯＣ（ＣＨ_３）_３；またはＰＯＣ、−ＣＨ_２ＯＣ（＝Ｏ）ＯＣＨ（ＣＨ_３）_２であり得る。また例えば、テノホビルは、Ｒ^３がＣＨ_３であり、そしてＲ^１、Ｒ^２、Ｒ^４、Ｒ^５、Ｒ^６、およびＲ^７がＨである構造を有する。ジアルキルホスホネートは、以下の方法に従って調製され得る：Ｑｕａｓｔら（１９７４）Ｓｙｎｔｈｅｓｉｓ ４９０；Ｓｔｏｗｅｌｌら（１９９０）Ｔｅｔｒａｈｅｄｒｏｎ Ｌｅｔｔ．３２６１；米国特許第５６６３１５９号。

Have,
Here, for PMEA, R ³ is H, and for PMPA, R ³ is C _{1 to} C ₆ alkyl, C _{1 to} C ₆ substituted alkyl, or CH ₂ OR ⁸ , where R ⁸ Are C _{1 to} C ₆ alkyl, C _{1 to} C ₆ hydroxyalkyl, or C _{1 to} C ₆ haloalkyl. R ⁶ and R ⁷ are independently H or C _{1 to} C ₆ alkyl. R ⁴ and R ⁵ are independently H, NH ₂ , NHR or NR ₂ , where R is a C _{1 to} C ₆ alkyl. R ¹ and R ² are independently H, C _l- C ₆ alkyl, C _l- C _6- substituted alkyl, C _6- C ₂₀ aryl, C _6- C _20- substituted aryl, C _6- C ₂₀ aryl alkyl. , C _{6 to} C _20- substituted arylalkyl, acyloxymethyl ester-CH ₂ OC (= O) R ⁹ (eg, POM), or acyloxymethyl carbonate-CH ₂ OC (= O) OR ⁹ (eg, POC). Yes, where R ⁹ is a C _{l to} C ₆ alkyl, a C _{l to} C ₆ substituted alkyl, a C _{6 to} C ₂₀ aryl or a C _{6 to} C ₂₀ substituted aryl. For example, R ¹ and R ² are pivaloyloxymethoxy, POM, -CH ₂ OC (= O) C (CH ₃ ) ₃ ; -CH ₂ OC (= O) OC (CH ₃ ) ₃ ; or POC, −CH ₂ OC (= O) OCH (CH ₃ ) ₂ can be. Also, for example, tenofovir has a structure in which R ³ is CH ₃ and R ¹ , R ² , R ⁴ , R ⁵ , R ⁶ , and R ⁷ are H. Dialkylphosphonates can be prepared according to the following methods: Quast et al. (1974) Synthesis 490; Stowell et al. (1990) Tetrahedron Lett. 3261; US Pat. No. 5,663,159.

The PMPA compound can be rich in enantiomers or pure (single stereoisomer), where the carbon atom with R ³ can be an R enantiomer or an S enantiomer. The PMPA compound can be a racemic compound (ie, a mixture of R and S stereoisomers).

Adefovir _(R 1 to R ₇ is H, 9-(2-phosphono-methoxyethyl) adenine) is an exemplary PMEA compound (US Patent No. 4,808,716, Nos. No. 4,724,233). As a bis-pivalate prodrug, adefovir dipivoxil (also known as bis-POM PMEA) (R _{3 to} R ₇ are H, R ₁ and R ₂ are -CH ₂ OC (= O) C (CH). ₃ ) ₃ , Pivoxil, POM, Pivaloyloxymethoxy) is effective against HIV and hepatitis B infections (US Pat. Nos. 5,663,159, 6,451,340). Adefovir dipivoxil, in combination with other compounds with anti-HIV activity, including PMPA, d4T, ddC, nelfinavir, ritonavir, and saquinavir, has demonstrated low to moderate synergistic inhibition of HIV replication. (Mulato et al. (1997) Antiviral Research 36: 91-97).

The present invention includes all enantiomers, diastereomers, racemic compounds, and stereoisomer-rich mixtures of PMEA and PMPA, as well as physiologically functional derivatives thereof.

Emtricitabine ((-) - cis-FTC, Emtriva ^TM) (single enantiomer of FTC) is a potent nucleoside reverse transcriptase inhibitor approved for the treatment of HIV (US Patent No. 5,047,407, the first No. 5179104, No. 5204466, No. 5210085, No. 5486520, No. 5538975, No. 5587480, No. 5618820, No. 5763606, No. 5814639, No. 5914331, No. 6114343, 6180639, 621004; WO 02/070518). This single enantiomer, emtricitabine, has the following structure:

エムトリシタビンについての化学名としては、以下が挙げられる：（−）−シス−ＦＴＣ；β−Ｌ−ヒドロキシメチル−５−（５−フルオロシトシン−１−イル）−１，３−オキサチオラン；（２Ｒ，５Ｓ）−５−フルオロ−１−［２−（ヒドロキシメチル）−１，３−オキサチオラン−５−イル］シトシン；および４−アミノ−５−フルオロ−１−（２−ヒドロキシメチル−［１，３］−（２Ｒ，５Ｓ）−オキサチオラン−５−イル）−１Ｈ−ピリミジン−２−オン。ＣＡＳ登録番号としては、以下が挙げられる：１４３４９１−５７−０；１４３４９１−５４−７。ＦＴＣは、オキサチオラン環の２位および５位に２つのキラル中心を含み、従って、光学異性体（すなわち、鏡像異性体）の２対の形態、およびその混合物の形態（ラセミ混合物を含む）で存在し得ることが注意されるべきである。従って、ＦＴＣは、シス異性体、もしくはトランス異性体、またはその混合物のいずれかであり得る。シス異性体およびトランス異性体の混合物は、異なる物理的特性を有するジアステレオマーである。各々のシス異性体およびトランス異性体は、２つの鏡像異性体のうちの１つとして、またはその混合物（ラセミ混合物を含む）として存在し得る。本発明は、全ての鏡像異性体、ジアステレオマー、ラセミ化合物、およびエムトリシタビンの立体異性体に富んだ混合物、ならびにその生理学的に機能的な誘導体を含む。例えば、本発明は、鏡像異性体（２Ｒ，５Ｓ，シス）−４−アミノ−５−フルオロ−１−（２−ヒドロキシメチル−１，３−オキサチオラン−５−イル）−（１Ｈ）−ピリミジン−２−オン（エムトリシタビン）およびその鏡像（２Ｓ，５Ｒ，シス）−４−アミノ−５−フルオロ−１−（２−ヒドロキシメチル−１，３−オキサチオラン−５−イル）−（１Ｈ）−ピリミジン−２−オンの１：１ラセミ混合物、または任意の相対量にある２つの鏡像異性体の混合物のような、生理学的に機能的な誘導体を含む。本発明はまた、ＦＴＣのシス型およびトランス型の混合物を含む。

Chemical names for emtricitabine include: (-)-cis-FTC; β-L-hydroxymethyl-5- (5-fluorocytosine-1-yl) -1,3-oxathiolane; (2R, 5S) -5-fluoro-1- [2- (hydroxymethyl) -1,3-oxathiolan-5-yl] cytosine; and 4-amino-5-fluoro-1- (2-hydroxymethyl- [1,3] ]-(2R, 5S) -oxathiolane-5-yl) -1H-pyrimidine-2-one. CAS Registry Numbers include: 143491-57-0; 143491-54-7. The FTC contains two chiral centers at the 2- and 5-positions of the oxathiorane ring and is therefore present in two pairs of optical isomers (ie, enantiomers) and in the form of mixtures thereof (including racemic mixtures). It should be noted that it can be done. Thus, the FTC can be either the cis isomer, the trans isomer, or a mixture thereof. Mixtures of cis and trans isomers are diastereomers with different physical properties. Each cis and trans isomer can exist as one of two enantiomers or as a mixture thereof (including a racemic mixture). The present invention includes all enantiomers, diastereomers, racemic compounds, and stereoisomer-rich mixtures of emtricitabine, as well as physiologically functional derivatives thereof. For example, the present invention presents the enantiomer (2R, 5S, cis) -4-amino-5-fluoro-1- (2-hydroxymethyl-1,3-oxathiolan-5-yl)-(1H) -pyrimidine-. 2-one (emtricitabine) and its enantiomers (2S, 5R, cis) -4-amino-5-fluoro-1- (2-hydroxymethyl-1,3-oxathiolan-5-yl)-(1H) -pyrimidine- It contains physiologically functional derivatives, such as a 2-on 1: 1 racemic mixture, or a mixture of two enantiomers in any relative amount. The present invention also includes a mixture of cis and trans forms of FTC.

Physiologically functional derivatives of emtricitabine have the following structures:

を有する１，３オキサチオランヌクレオシドを含む。

Includes 1,3 oxathiolane nucleosides with.

In the 1,3 oxathiolane nucleoside structure described above, B can pair with a complementary nucleobase or nucleobase analog (eg, purine, 7-deazapurine, or pyrimidine) to form a Watson-Crick hydrogen bond. A possible nucleobase containing any nitrogen-containing heterocyclic moiety. Examples of B include the following naturally occurring nucleobases: adenine, guanine, cytosine, uracil, timine, and trace components and analogs of naturally occurring nucleobases (eg, 7-deazaadenine, 7-deazaguanine). , 7-Daza-8-Azaguanin, 7-Daza-8-Azaadenin, Cytosine, Nebulaline, Nitropylol, Nitroindole, 2-Aminopurine, 2-Amino-6-Chloroprin, 2,6-Diaminopurine, Hipoxatin, Pseudouridine, 5-fluorocytosine, 5-chlorocytosine, 5-bromocytosine, 5-iodositosine, pseudocytosine, pseudo-cytositosine, 5-propynylcytosine, isocytosine, isoguanine, 7-deazaguanine, 2-thiopyrimidine, 6- thioguanine, 4-thiothymine, 4-thiouracil, ^{O 6} - methylguanine, ^{N 6} - methyl adenine, ^{O 4} - methylthymine, 5,6-dihydrothymine, 5,6-dihydrouracil, 4-methylindole, pyrazolo [3, 4-D] Cytosine (US Pat. Nos. 6,143,877 and 6,127,121; WO 01/38584), and Cytosine (Fasman (1989) in Practical Handbook of Biochemistry and Molecular Biol. -394, CRC Press, Boca Raton, Fl)).

Nucleobase B can be present via covalent bonds between N-9 of purines (eg, adenine-9-yl and guanine-9-yl) or between N-1 of pyrimidines in the configuration of naturally occurring nucleic acids. Can be attached to 1,3 oxathiolan moieties via covalent bonds (eg, thymine-1-yl and cytosine-1-yl) (Blackburn, G. and Gait, M. ed., "DNA and RNA structure" in Nucleic. Acids in Chemistry and Biology, 2nd Edition, (1996) Oxford Universality Press, pp. 15-81).

Further, in the above 1,3 oxathiolane nucleoside structure, R is H, C _{1 to} C ₁₈ alkyl, C _{1 to} C ₁₈ substituted alkyl, C _{2 to} C ₁₈ alkenyl, C _{2 to} C ₁₈ substituted alkyne, C. _{2 to} C ₁₈ alkynyl, C _{2 to} C ₁₈ substituted alkynyl, C _{6 to} C ₂₀ aryl, C _{6 to} C ₂₀ substituted aryl, C _{2 to} C ₂₀ heterocycle, C _{2 to} C ₂₀ substituted heterocycle, phosphonate, phosphophosphonate , Diphosphophosphonate, phosphate, diphosphate, triphosphate, polyethyleneoxy, or prodrug moiety.

Physiologically functional derivatives of emtricitabine also include 3TC (lamivudine, Epivir®). 3TC is a US-approved reversal transcription enzyme inhibitor for the treatment of HIV-1 infections in combination with AZT as Comvivir® (GlaxoSmithKline). U.S. Pat. Nos. 5859021; 5905082; 6177435; 5627186; 6417191. Lamivudine (US Pat. Nos. 5,587,480, 5696254, 5618820, 5756706, 5744596, 5681164, 5466806, 5151426) has the following structure. ..

例えば、いくつかの治療的使用について、３ＴＣは、テノホビルＤＦまたはテノホビルＤＦの生理学的に機能的な誘導体と組み合わせた、エムトリシタビンの生理学的に機能的な誘導体であり得る。

For example, for some therapeutic uses, 3TC can be a physiologically functional derivative of emtricitabine in combination with tenofovir DF or a physiologically functional derivative of tenofovir DF.

Tenofovir DF and emtricitabine, as well as their physiologically functional derivatives, can be present in the keto or enol tautomeric form, and the use of any of the tautomeric forms is within the scope of the invention. It is recognized that there is. Tenofovir DF and emtricitabine are typically utilized in combinations of the invention that are substantially free of the corresponding enantiomers (ie, there are less than about 5 w / w% of the corresponding enantiomers).

(Prodrug)
The present invention includes all prodrugs of tenofovir and emtricitabine. An exemplary prodrug of tenofovir is tenofovir disoproxil fumarate (TDF, Viread®). Many structurally diverse prodrugs have been described for phosphonic acids (Freeman and Ross, Medicinal Chemistry 34: 112-147 (1997)). A commonly used prodrug class is the acyloxyalkyl ester, which was first used as a prodrug strategy for carboxylic acids, followed by Farquhar et al. (1983) J. Mol. Pharm. Sci. 72: 324; also applied to phosphate and phosphonate by U.S. Pat. Nos. 4,816,570, 49,688, 569,159, and 579,756. Subsequently, acyloxyalkyl esters were used to deliver phosphonic acid across cell membranes and to enhance oral bioavailability. Alkoxycarbonyloxyalkyl esters, a close variant of the acyloxyalkyl ester strategy, can also enhance oral bioavailability as a prodrug portion of the combination compounds of the invention. Aryl esters of phosphorus groups (particularly phenyl esters) have been reported to enhance oral bioavailability (DeLambert et al. (1994) J. Med. Chem. 37: 498). Phenyl esters containing carboxylic acid esters at the ortho position of the phosphate have also been described (Khamney and Torrence, (1996) J. Med. Chem. 39: 4109-4115). Benzyl esters are reported to produce the original phosphonic acid. In some cases, substituents at the ortho or para position can promote hydrolysis. A benzyl analog with an acylated phenol or an alkylated phenol can produce a phenolic compound through the action of an enzyme (eg, esterase, oxidase, etc.). The phenolic compound is then cleaved at the benzylic CO bond to give the phosphate and quinone methide intermediates. An example of this class of prodrugs is Mitchell et al. (1992) J. Mol. Chem. Soc. Perkin Trans. I 2345; Described by Brook et al., WO 91/19721. Yet other benzylic prodrugs have been described as containing a carboxylic acid ester-containing group attached to benzylic methylene (Glazier et al., WO 91/19721). Thio-containing prodrugs have been reported to be useful for intracellular delivery of phosphonate drugs. These proesters contain an ethylthio group, in which the thiol group is either esterified with an acyl group or combined with another thiol group to form a disulfide. Deesterification or reduction of this disulfide produces a free thio intermediate, which is subsequently degraded to phosphoric acid and episulfide (Puech et al. (1993) Experimental Res., 22: 155-174). Benzaria et al. (1996) J. Med. Chem. 39: 4985). Cyclic phosphonic acid esters have also been described as prodrugs of phosphorus-containing compounds.

Prodrug esters according to the invention are independently selected from the following groups: (1) mono-phosphates, di-phosphates, and tri-phosphates of tenhovir or emtricitabin or any other compound. Esters (tenohobil or emtricitabine or any other compound may be the mono-phosphate ester, di-phosphate ester, or tri-phosphate ester (directly or indirectly) upon administration to a human subject. (To); (2) carboxylic acid esters, (3) sulfonic acid esters (eg, alkylsulfonyl or aralkylsulfonyl (eg, methanesulfonyl)); (4) amino acid esters (eg, alanine, etc.) L-Valyl or L-Isoleucyl); (5) Phosphonate Ester; and (6) Phosphon Amidate Ester.

Ester group (1) to (6) may be replaced by the following: straight-chain or branched _C 1 _{-C 18} alkyl (e.g., methyl, n- propyl, t- butyl, or n- butyl) C _{3 to} C ₁₂ cycloalkyl; alkoxyalkyl (eg, methoxymethyl); arylalkyl (eg, benzyl); aryloxyalkyl (eg, phenoxymethyl); C _{5 to} C ₂₀ aryl (eg, as needed) For example, _halogen, C 1 -C _{4 alkyl,} C 1 -C ₄ alkoxy or amino) substituted phenyl); acyloxymethyl esters ^{_{-CH 2 OC (= O) R}} 9 ( e.g., POM), or acyloxymethyl Carboxyl ester-CH ₂ OC (= O) OR ⁹ (eg POC), where R ⁹ is C _{1 to} C ₆ alkyl, C _{1 to} C ₆ substituted alkyl, C _{6 to} C ₂₀ aryl or C ₆ to. it is a C ₂₀ substituted aryl. For example, the ester group can be: -CH ₂ OC (= O) C (CH ₃ ) ₃ , -CH ₂ OC (= O) OC (CH ₃ ) ₃ , or -CH ₂ OC (= O). OCH (CH ₃ ) ₂ .

Exemplary aryl moieties present in such esters include phenyl or substituted phenyl groups. Many phosphate prodrug moieties are described in US Pat. No. 6,316,262; Jones et al. (1995) Experimental Research 27: 1-17; Kusera et al. (1990) AIDS Res. Hum. Retro Viruses 6: 491-501; Piantadosi et al. (1991) J. Mol. Med. Chem. 34: 1408-14; Hosteller et al. (1992) Antimiclob. Agents
Chemother. 36: 2025-29; Hostettler et al. (1990) J. Mol. Biol. Chem. 265: 61127; and Siddiqui et al. (1999) J. Mol. Med. Chem. 42: 4122-28.

A pharmaceutically acceptable prodrug is metabolized in the host (eg, hydrolyzed or oxidized by enzymatic action or by either general acid solvolysis or base solvolysis). , A compound that forms an active ingredient. A representative example of a prodrug of the active ingredient of the combination of the present invention has a biologically unstable protecting group at the functional group moiety of this active compound. Prodrugs include oxidation, reduction, amination, deaminolation, esterification, deesterification, alkylation, dealkylation, acylation, deacylation, phosphorylation, dephosphorylation, or other functional group exchange or Includes compounds that can be converted (including the formation or cleavage of chemical bonds of this prodrug).

(Chemical stability of pharmaceutical prescriptions)
The chemical stability of the active ingredient in a pharmaceutical formulation is associated with minimizing the formation of impurities and ensuring a proper shelf life. The active ingredients in the pharmaceutical formulations of the present invention, tenofovir disoproxil fumarate and emtricitabine, have relatively low pKa values (indicating the potential to cause acid hydrolysis of the active ingredient). Emtricitabine with a pKa of 2.65 (available at Emtricita ^TM Product Insert, Gilead Sciences, Inc. 2003, Gilead.com) undergoes hydrolytic deamination of the 5-fluorocytosine nucleobase and 5-fluorouridine. Form a nucleic acid base. Tenofovir disoproxil fumarate with a pKa of 3.75 (Yuan L. et al., "Degradation Kinetics of Oxycarbonymyl Prodrugs of Phosphonates in Solution", Phosphonates in Solution, Vol. The adenine nucleic acid base undergoes hydrolytic deamination of the out-of-ring amine and one or both of the POC ester groups (US Pat. No. 5,922,695). It is desirable to formulate a therapeutic combination of tenofovir disoproxil fumarate with emtricitabine, and its physiologically functional derivatives, with minimal impurities and adequate stability.

The combinations of the present invention provide a pharmaceutical dosage form of the combination that is chemically stable against the following acid degradation: (1) the first component (eg, tenofovir disoproxil fumarate, and physiologically. (Functional derivatives); (2) Second component (eg, emtricitabine, physiologically functional derivative); and (3) Third component having antiviral activity, if desired. The third component includes anti-HIV agents and includes protease inhibitors (PIs), nucleoside reverse transcriptase inhibitors (NRTIs), non-nucleoside reverse transcriptase inhibitors (NNRTIs), and integrase inhibitors. An exemplary third active ingredient administered in combination with the first ingredient and the second ingredient is shown in Table A. The first component and the second component are as defined in the upper section entitled "Combination Active Ingredients".

(salt)
Any reference to any compound in the compositions of the invention also includes any physiologically acceptable salt thereof. Examples of physiologically acceptable salts of tenofovir DF, emtricitabin and their physiologically functional derivatives include suitable bases (eg, alkali metals (eg, sodium), alkaline earth metals (eg, magnesium)). , ammonia and _NX ^{4 +} (wherein, X is _C 1 -C ₄ alkyl)), or organic acids (e.g., fumaric acid, acetic acid, salts derived from succinic acid). Physiologically acceptable salts of hydrogen atoms or amino groups include organic carboxylic acids (eg acetic acid, benzoic acid, lactic acid, fumaric acid, tartaric acid, maleic acid, malonic acid, malic acid, isetioic acid, lactobionic acid, succinate). Acids), organic sulfonic acids (eg, methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, and p-toluenesulfonic acid), and salts of inorganic acids (eg, hydrochloric acid, sulfuric acid, phosphoric acid, or sulfamic acid). Be done. Physiologically acceptable salts of the compounds of the hydroxy group, suitable cations (e.g., Na ⁺ and _NX ^{4 +} (wherein X is independently selected from H or _C 1 -C ₄ alkyl group )) And an anion of this compound.

For therapeutic use, the salts of the active ingredients in the combinations of the invention are physiologically acceptable. That is, they are salts derived from physiologically acceptable acids or bases. However, salts of acids or bases that are not physiologically acceptable can also be found for use, for example, in the preparation or purification of physiologically acceptable compounds. All salts, whether derived from physiologically acceptable acids or bases, are within the scope of the invention.

(Administration of prescription)
The combination of active ingredients can be administered alone or separately as a monotherapy, but it is preferred to administer this combination of active ingredients as a pharmaceutical co-prescription. Two parts or a combination of three parts can be administered simultaneously or sequentially. When administered sequentially, this combination may be administered in one, two, or three doses.

Preferably, the two parts, or a combination of the three parts, are administered in a single pharmaceutical dosage form. More preferably, the combination of the two parts is administered as a single oral dosage form, and the combination of the three portions is administered as two identical oral dosage forms. Examples include a single tablet of tenofovir disoproxil fumarate and emtricitabine, or two tablets of tenofovir disoproxil fumarate, emtricitabine, and emtricitabine.

Combination compounds deliver the compounds simultaneously by (1) the combination of compounds in the co-formulation, or (2) alternately (ie, continuously, sequentially, in parallel or simultaneously) in separate pharmaceutical formulations. ) It is recognized that it can be administered. In alternating treatments, delays in administering a second active ingredient, and optionally a third active ingredient, should not, for example, lose the benefit of the synergistic therapeutic effect of the active ingredient combination. By the method of administration (1) or (2), ideally the combination should be administered to achieve the highest plasma concentration of each active ingredient. A once-daily one-tablet regimen (one pile once-per-day regimen) by administration of a combination co-prescription may be feasible for some HIV-positive patients. The effective maximum plasma concentration of the active ingredient of the combination is in the range of about 0.001 μM to 100 μM. Optimal plasma concentrations can be achieved by the formulation and dosing regimen prescribed for a particular patient. Tenofovir DF and emtricitabine, or physiologically functional derivatives of any of these, are administered individually, in multiples, or in any combination of these, whether given simultaneously or sequentially. Getting is also understood. Generally, during alternating treatment (2), each compound in an effective dose is administered sequentially, and in co-prescription treatment (1), two or more compounds in an effective dose are administered together.

(Combination prescription)
When the individual components of the combination are administered separately, they are generally represented as pharmaceutical formulations, respectively. The following references in the specification to a formulation refer to a formulation containing either of these combinations or any of these constituent compounds, unless otherwise indicated. Administration of a single patient pack of each formulation, or a combination of the invention by multiple patient packs, within a package publication that transforms the patient into the correct use of the invention is a desired further feature of the invention. Is understood to be. The invention also includes two packs comprising a formulation of tenofovir disoproxil fumarate and emtricitabine, or a physiologically functional derivative of either or both, in connection with separate administration.

The combinational treatments of the present invention include: (1) a combination of tenofovir DF and emtricitabine, or (2) a combination comprising a physiologically functional derivative of either or both of these.

The combination may be administered in a unit dose formulation comprising a fixed amount of each active pharmaceutical ingredient for regular (eg, daily) or partial administration (subdose) of this active ingredient.

Pharmaceutical formulations according to the invention include combinations according to the invention, along with one or more pharmaceutically acceptable carriers or excipients and optionally other therapeutic agents. The pharmaceutical formulation containing the active ingredient can be in any form suitable for the method intended for administration. When used for oral use, for example, tablets, lozenges, lozenges, aqueous or oil suspensions, dispersible powders or granules, emulsions, hard or soft capsules, syrups or elixirs. (Remington's Pharmaceutical Sciences (Mack Publishing Co., Easton, PA). Compositions intended for oral use are prepared according to any method known in the art for the production of pharmaceutical compositions. And such compositions may include one or more agents, including antioxidants, sweeteners, flavoring agents, colorants and preservatives, to provide a palatable preparation. Tablets containing the active ingredient mixed with non-toxic, pharmaceutically acceptable excipients suitable for the manufacture of tablets are acceptable. These excipients are, for example, inert diluents ( For example, calcium carbonate or sodium carbonate, lactose, lactose monohydrate, croscarmellose sodium, povidone, calcium phosphate or sodium phosphate); granulators and disintegrants (eg, corn starch or alginic acid); binders (eg, corn starch or alginate) , Cellulose, microcrystalline cellulose, starch, gelatin or acacia); and can be a lubricant (eg, magnesium stearate, stearic acid or talc). Tablets can be uncoated or disintegrated in the gastrointestinal tract. And may be coated by known techniques (including microencapsulation) to delay absorption and thereby provide long-lasting action, eg, time delay alone or with wax. A substance (eg, glycerin monostearate, or glycerin distearate) can be used.

Formulations for oral use also have the active ingredient as a hard gelatin capsule in which the active ingredient is mixed with an inert solid diluent (eg, pregelatinized starch, calcium phosphate or kaolin), or the active ingredient is water or oil. It can be shown as a soft gelatin capsule mixed with the vehicle (peanut oil, liquid paraffin, or olive oil).

The aqueous suspension of the present invention contains an active substance mixed with an excipient suitable for producing an aqueous suspension. Such excipients include suspending agents (eg, sodium carboxymethyl cellulose, methyl cellulose, hydroxypropyl methyl cellulose, sodium alginate, polyvinylpyrrolidone, tragacant rubber, gum arabic), and dispersants or wetting agents (eg, naturally occurring). Phosphatides (eg, lecithin), condensation products of alkylene oxides and fatty acids (eg, polyoxyethylene stearate), condensation products of ethylenetoxide and long-chain fatty alcohols (eg, heptadecaethyleneoxycetanol), Condensation products of ethylene oxide with partial esters derived from fatty acids and hexitol anhydrides (eg, polyoxyethylene sorbitan monooleate). The aqueous suspension also comprises one or more preservatives (eg, ethyl p-hydroxybenzoate, or n-propyl p-hydroxybenzoate), one or more colorants, and one or more flavoring and flavoring agents. And may include one or more sweeteners (eg, sucralose, sucralose or saccharin).

Oily suspensions can be formulated by suspending the active ingredient in vegetable oils (eg, peanut oil, olive oil, sesame oil or coconut oil) or in mineral oils (eg, liquid paraffin). This oral suspension may contain a thickener (eg, beeswax, solid paraffin, or cetyl alcohol). Sweeteners and flavoring agents as shown above can be added to provide a palatable oral preparation. These compositions can be preserved by the addition of antioxidants (eg, ascorbic acid, BHT, etc.).

Suitable for the preparation of aqueous suspensions by the addition of water, the dispersible powders and granules of the present invention are mixed with dispersants or wetting agents, suspending agents, and one or more preservatives to produce the active ingredient. provide. Suitable dispersants or wetting agents and suspending agents are exemplified by those disclosed above. Additional excipients (eg, sweeteners, flavoring agents and colorants) may also be indicated.

The pharmaceutical compositions of the present invention can also be in the form of oil-in-water emulsions or liposome formulations. The oil phase can be a vegetable oil (eg, olive oil or peanut oil), a mineral oil (eg, liquid paraffin), or a mixture thereof. Suitable emulsifiers include naturally occurring rubbers (eg, arabic rubber and tragacant rubber), naturally occurring phosphatides (eg, soy lecithin), esters or partial esters derived from fatty acids and hexitol anhydrides (eg, sorbitan). Monooleates), as well as condensation products of these partial esters with ethylene oxide (eg, polyoxyethylene sorbitan monooleates). The emulsion may also contain sweeteners and flavoring agents. Syrups and elixirs can be formulated with sweeteners (eg, glycerol, sorbitol, or sucrose). Such formulations may also include mucilages, preservatives, flavoring agents or colorants.

The pharmaceutical composition of the present invention may be in the form of a sterile injectable preparation (eg, a sterile injectable aqueous suspension or a sterile injectable oily suspension). The suspension can be formulated according to known techniques with the appropriate dispersants or wetting or suspending agents described above. This sterile injectable preparation is also a sterile injectable solution or sterile injectable suspension in a non-toxic, parenterally acceptable diluent or solvent (eg, a solution in 1,3-butanediol). It can be a turbid solution or can be prepared as a lyophilized powder. Acceptable vehicles and solvents that can be used are water, Ringer's solution, and isotonic sodium chloride solution. In addition, sterile non-volatile oils can be commonly used as solvents or suspension media. For this purpose, any non-irritating non-volatile oil can be used, such as monoglyceride or diglyceride. In addition, fatty acids such as oleic acid can be used in the preparation of injectables as well.

The pharmaceutical compositions of the present invention can be parenteral (eg, intravenously, intraperitoneally, intrathecally, intraventricularly, intrasternally, intracranial, intramuscularly, or It can be injected (subcutaneously) or the pharmaceutical compositions of the invention can be administered by injection techniques. The pharmaceutical compositions of the present invention are most often used in the form of sterile aqueous solutions that may contain other substances (eg, salts or glucose sufficient to make the solution isotonic with blood). This aqueous solution should be adequately buffered (preferably to a pH of 3-9) if necessary. Preparation of a suitable parenteral formulation under sterile conditions is easily accomplished by standard pharmaceutical techniques well known to those of skill in the art.

The pharmaceutical compositions of the present invention can also be administered intranasally or by inhalation and are suitable propellants such as dichlorodifluoromethane, trichlorofluoromethane, dichlorotetrafluoroethane, hydrofluoroalkane (eg, dichlorodifluoromethane, trichlorofluoromethane, dichlorotetrafluoroethane). Presentation of a dry powder inhaler or aerosol spray from a pressure vessel or nebulizer using, for example, 1,1,1,2-tetrafluoroethane (HFC134a)), carbon dioxide, or other suitable gas). It is conveniently delivered in the form of presentation). In the case of pressurized aerosols, the unit of administration can be determined by providing a valve that delivers a predetermined amount. The pressurized vessel or atomizer may contain a solution or suspension of the composition, for example using a mixture of ethanol and propellant as the solvent. It may further include a lubricant (eg, sorbitan trioleate). Capsules and cartridges (eg, made from gelatin) for use in inhalers or insufflators are combined with compounds of formula (I) and suitable powder bases (eg, lactose or starch). Can be formulated to include a powder mixture of. Aerosol formulations or dry powder formulations are preferably arranged so that each predetermined dose or "puff" comprises 20 μg to 20 mg of the composition for delivery to the patient. Overall daily doses with aerosols range from 20 μg to 20 mg, which can be administered in single doses, more usually in divided doses, throughout the day.

The amount of active ingredient that can be combined with the carrier material to make a single dosage form will vary depending on the host being treated and the particular dosage form. For example, timed release formulations intended for oral administration to humans use appropriate and convenient amounts of carrier material that can vary from about 5% to about 95% by weight (weight: weight) of the total composition. It may contain from about 1 mg to 1000 mg of formulated active material. The pharmaceutical composition can be prepared to provide an easily measurable amount for administration. For example, an aqueous solution intended for intravenous infusion may contain from about 3 μg to 500 μg of active ingredient per mL of solution so that an appropriate volume of infusion can occur at a rate of about 30 mL / hour. As noted above, the formulations of the invention suitable for oral administration are individual units (eg, capsules, cashiers, or tablets each containing a predetermined amount of active ingredient; powder or granules. It can be indicated as a solution or suspension in an aqueous or non-aqueous liquid; or an oil-in-water liquid emulsion or a water-in-oil emulsion). This active ingredient can also be administered as a bolus, lick or paste.

The combinations of the invention can conveniently be presented as pharmaceutical formulations in unit dosage form. A convenient unit dose formulation comprises the active ingredient in any amount (eg, but not limited to, 10 mg to 300 mg) of about 1 mg to 1 g each. The synergistic effect of tenofovir DF in combination with emtricitabine can be achieved over a wide range (eg 1: 50-50: 1 (eg 1: 50-50: 1 (tenofovir DF: emtricitabine)). In one embodiment, this ratio can range from about 1:10 to 10: 1. In another embodiment, the weight / weight ratio of tenofovir to emtricitabine in co-prescribed combination dosage forms (eg, pills, tablets, caplets, or capsules) is about 1 (ie, approximately equal amounts). Tenofovir DF and emtricitabine). In other exemplary co-formulations, there may be more or less tenofovir than FTC. For example, 300 mg tenofovir DF and 200 mg emtricitabine can be co-prescribed in a ratio of 1.5: 1 (tenofovir DF: emtricitabine). In one embodiment, the compounds are used in combination in an amount that exhibits antiviral activity when used alone. The exemplary formulations A, B, C, D, E, and F (Examples) have a ratio of 12: 1 to 1: 1 (tenofovir DF: emtricitabine). The exemplary formulations A, B, C, D, E, and F use amounts of tenofovir DF and emtricitabine in the range of 25 mg to 300 mg. Other ratios and amounts of compounds in this combination are intended within the scope of the invention.

Unit dosage forms may further comprise tenofovir DF and emtricitabine, or physiologically functional derivatives of any of these, as well as pharmaceutically acceptable carriers.

The amount of active ingredient in the combination of the invention required for use in treatment varies according to various factors, including the nature of the condition being treated, as well as the age and condition of the patient, and ultimately. It will be recognized by those skilled in the art that it is at the discretion of the attending physician or health care manager. Factors to be considered include the nature of the route of administration and formulation, the weight, age and general condition of the animal, and the nature and severity of the disease to be treated. For example, in a phase I / phase II monotherapy study of emtricitabine, patients received doses ranging from 25 mg to 200 mg twice daily for 2 weeks. Over 98% (1.75 log 10) virus suppression was observed at each dose regimen of 200 mg and above. A daily dose of 200 mg of emtricitabine reduced the viral load by an average of 99% (1.92 log 10). Viread® (tenofovir DF) has been approved by the FDA as a 300 mg oral tablet for the treatment and prevention of HIV infection. Emtriva ^TM (emtricitabine), for the treatment of HIV, has been approved by the FDA as an oral tablet 200 mg.

It is also possible to combine any two active ingredients in a unit dosage form for co-administration or sequential administration with a third active ingredient. The combination of the three parts can be administered simultaneously or sequentially. When administered sequentially, this combination can be administered in two or three doses. The third active ingredient has anti-HIV activity, and the third active ingredient includes protease inhibitor (PI), nucleoside reverse transcriptase inhibitor (NRTI), non-nucleoside reverse transcriptase inhibitor (NNRTI), and integrase. Lase inhibitors can be mentioned. An exemplary third active ingredient administered in combination with tenofovir DF, emtricitabine, and their physiologically functional derivatives is shown in Table A.

(Table A)
5,6 dihydro-5-azacitidine
5-Aza 2'deoxycytidine
5-azacitidine 5-yl-carbocyclic 2'-deoxyguanosine (BMS200,475)
9 (arabinofuranosyl) guanine; 9- (2'deoxyribofuranosyl) guanine
9- (2'-deoxy2'fluororibofuranosyl) -2,6-diaminopurine
9- (2'-deoxy 2'fluororibofuranosyl) guanine
9- (2'-deoxyribofuranosyl) -2,6 diaminopurine 9- (arabinofuranosyl) -2,6 diaminopurine abacavir, Ziagen®
Acyclovir, ACV; 9- (2-hydroxyethoxylmethyl) guanine adefovir dipivoxil, Hepsera®
Amdoxyville, DAPD
Amprenavir, Agerise®
Ala A; 9-β-D-arabinofuranosyl adenine (vidarabine)
Atazanavir Sulfate (Reyataz®)
AZT; 3'-azido-2', 3'-zideoxythymidine, zidovudine, (Retrovir®)
BBCG; (. +-.)-(1a, 2b, 3a) -9- [2,3-bis (hydroxymethyl) cyclobutyl] guanine
BMS200,475; 5-yl-carboncyclic 2'-deoxyguanosine bucyclovir; (R) 9- (3,4-dihydroxybutyl) guanine
BvaraU; 1-β-D-arabinofuranosyl-E-5- (2-bromovinyl) uracil (sorivudine)
Caranolide A
Coupler billin
CDG; Carbocyclic 2'-Deoxyguanosine
Sidhovir, HPMPC; (S) -9- (3-hydroxy-2-phosphonylmethoxypropyl) cytosine
Klebdin, L-FMAU; 2'-fluoro-5-methyl-β-L-arabino-furanosyl uracil
Combivir® (lamivudine / zidovudine) citalene; [1- (4'-hydroxy-1', 2'-butadienyl) cytosine] d4C; 3'-deoxy-2', 3'-didehydrocytidine
DAPD; (-)-β-D-2,6-diaminopurine dioxolane
ddA; 2', 3'-dideoxyadenosine
ddAPR; 2,6-diaminopurine-2', 3'-dideoxyriboside
ddC; 2', 3'-dideoxycytidine (zalcitabine)
ddI; 2', 3'-dideoxyinosine, didanosine, (Videx®, Videx® EC)
Delavirdine, Rescriptor®
Didanosine, ddI, Videx®; 2', 3'-dideoxyinosine
DXG; dioxolane guanosine
E-5- (2-Bromovinyl) -2'-deoxyuridine
Efavirenz, Sustiver®
Enfuvirtide, Fuzeon®
F-ara-A; fluoroarabinosyl adenosine (fludarabine)
FDOC; (-)-β-D-5-fluoro-1- [2- (hydroxymethyl) -1,3-dioxolane] cytosine
FEAU; 2'-deoxy-2'-fluoro-1-β-D-arabinofuranosyl-5-ethyluracil
FIAC; 1- (2-deoxy-2-fluoro-β-D-arabinofuranosyl) -5-iodocytosine FIAU; 1- (2-deoxy-2-fluoro-β-D-arabinofuranosyl)- 5-Iodouridine
FLG; 2', 3'-dideoxy-3'-fluoroguanosine
FLT; 3'-deoxy-3'-fluorothymidine
Fludarabine; F-ara-A; fluoroarabinosyl adenosine
FMAU; 2'-fluoro-5-methyl-β-L-arabino-furanosyl uracil
FMdC
Hoscanet; Phosphonoic acid, PFA
FMPPA; 9- (3-fluoro-2-phosphonylmethoxypropyl) adenine
Ganciclovir, GCV; 9- (1,3-dihydroxy-2-propoxymethyl) guanine
GS-7340; 9- [R-2-[[(S)-[[(S) -1- (isopropoxycarbonyl) ethyl] amino] -phenoxyphosphinyl] methoxy] propyl] adenine
HPMPA; (S) -9- (3-hydroxy-2-phosphonylmethoxypropyl) adenine
HPMPC; (S) -9- (3-Hydroxy-2-phosphonylmethoxypropyl) cytosine (Sidhovir)
Hydroxyurea, Droxya®
Indinavir, Crixivan®
Kaletra® (Lopinavir / Ritonavir)
Lamivudine, 3TC, Epivir ^TM ; (2R, 5S, cis) -4-amino-1- (2-hydroxymethyl-1,3-oxathiolan-5-yl)-(1H) -pyrimidine-2-one
L-d4C; L-3'-deoxy-2', 3'-didehydrocytidine
L-ddC; L-2', 3'-dideoxycytidine
L-Fd4C; L-3'-deoxy-2', 3'-didehydro-5-fluorocytidine L-FddC; L-2', 3'-dideoxy-5-fluorocytidine lopinavir
Nelfinavir, Viracept® Nevirapine, Viramune®
Oxetanosin A; 9- (2-deoxy-2-hydroxymethyl-β-D-erythro-oxetanosyl) adenine
Oxetanosin G; 9- (2-deoxy-2-hydroxymethyl-β-D-erythro-oxetanosyl) guanine pencyclovir
PMEDAP; 9- (2-phosphonylmethoxyethyl) -2,6-diaminopurine
PMPA, tenofovir; (R) -9- (2-phosphonylmethoxypropyl) adenine
PPA; ribavirin phosphonoacetate; 1-β-D-ribofuranosyl-1,2,4-triazole-3-carboxamide
Ritonavir, Norvir®
Saquinavir, Invirase®, Fortovese®
Sorivudine, BvaraU; 1-β-D-arabinofuranosyl-E-5- (2-bromovinyl) uracil
Stavudine, d4T, Zerit®; 2', 3'-didehydro-3'-deoxythymidine trifluorothymidine, TFT; trifluorothymidine Trizivir® (abacavir sulfate / lamivudine / zidovudine) Vidarabin, Ala A 9-β-D-arabinofuranosyl adenin
Zalcitabine, Hivid®, ddC; 2', 3'-dideoxycytidine
Zidovudine, AZT, Retrovir®; 3'-azido-2', 3'-dideoxythymidine
Zonavir; 5-propynyl-1-arabinosyl uracil.

Another aspect of the invention is tenofovir DF, FTC, and 9-[(R) -2-[[(S)-[[(S) -1- (isopropoxycarbonyl) ethyl] amino] phenoxyphosphinyl. ] Methoxy] propyl] adenine (also referred to herein as GS-7340) is a combination of three moieties. GS-7340 has the following structure.

ＧＳ−７３４０は、テノホビルのプロドラッグであり、共有に係る係属中の出願である米国出願番号第０９／９０９，５６０（２００１年７月２０日出願）、およびＢｅｃｋｅｒらＷＯ ０２／０８２４１の対象である。

GS-7340 is a prodrug of tenofovir and is subject to US application number 09/909,560 (filed July 20, 2001), which is a pending application for sharing, and Becker et al. WO 02/08241. is there.

For example, a unit dose of the three components may include 1 mg to 1000 mg tenofovir disoproxil fumarate, 1 mg to 1000 mg emtricitabine, and 1 mg to 1000 mg a third active ingredient. As a further feature of the invention, the unit dosage form further comprises tenofovir DF, emtricitabine, a third active ingredient, or a physiologically functional derivative of the third active ingredient, and a pharmaceutically acceptable carrier. obtain.

The combination of the present invention allows patients to be even more free from multi-dose dosing regimens, reducing the essential efforts required to remember and adhere to complex daily dosing times and dosing schedules. .. By combining tenofovir disoproxil fumarate and emtricitabine in a single dosage form, the desired daily regimen can be given once a day or more than once a day in partial doses (sub-dose). ) Can be shown. The co-prescribed combination of tenofovir DF and emtricitabine can be administered once daily as a single pill.

A further aspect of the invention is an information package containing at least one active ingredient (a physiologically functional derivative of tenofovir disoproxil fumarate, emtricitabine, or a combination) and instructions for using the combination of the invention. Or a patient pack with product listings.

Separation of the active ingredient in pharmaceutical powders and granules is a widely recognized problem that can result in uneven dispersion of the active ingredient in the final dosage form. Several key factors contributing to separation are particle size, particle morphology and particle density. Separation is particularly troublesome when attempting to formulate a single, uniform tablet containing multiple active ingredients with different densities and different particle sizes. Glidants are substances traditionally used to improve the flow properties of granules and powders by reducing interparticle friction. Lieberman, Lachman and Schwartz, Pharmaceutical Dose Forms: Tablets, Volume 1, p. See 177-178 (1989), incorporated herein by reference. The flow enhancer is typically added to the pharmaceutical composition just prior to tablet compression to facilitate the flow of the granular material into the die cavity of the tablet press. Flow accelerators include: colloidal silicon dioxide, asbestos-free talc, sodium aluminosilicate, calcium silicate, powdered cellulose, microcrystalline cellulose, corn starch, sodium benzoate, calcium carbonate, magnesium carbonate, Metal stearate, calcium stearate, magnesium stearate, zinc stearate, stearowet C, starch, starch 1500, magnesium lauryl sulfate, and magnesium oxide. An exemplary tablet formulation A has colloidal silicon dioxide (Examples). Flow enhancers can be used to increase and assist the uniformity of the blend composition in the formulation of anti-HIV drugs (US Pat. No. 6,113,920). The novel compositions of the present invention may include a flow enhancer to provide and maintain homogeneity of the active ingredient during the pre-compression operation of the tablet.

To use a pharmaceutical formulation in a fully homogenized form, and the pharmaceutical formulation in combination with the active ingredients tenofovir DF and emtricitabine, or their physiologically functional derivatives. Provides a method of. An object of the present invention is to utilize a flow enhancer to reduce the separation of active ingredients in a pharmaceutical formulation during precompression material manipulation. Another object of the present invention is to provide a pharmaceutical formulation in which the active ingredients tenofovir DF and emtricitabine, or physiologically functional derivatives thereof, are combined with a pharmaceutically acceptable flow enhancer. It is to provide a mixture characterized by the uniformity of a scale that is generally acceptable.

The prescriptions are oral, rectal, nasal, topical (including transdermal, buccal and sublingual), vaginal or parenteral (subcutaneous, intramuscular, intravenous and cutaneous). Includes suitable formulations for (including oral administration). This formulation can be conveniently presented in unit dosage form and can be prepared by any method well known in the pharmaceutical art. Such methods present additional features of the invention and include the step of combining the active ingredient with the carrier. This carrier constitutes one or more auxiliary components and maintains chemical stability. In general, the formulation is prepared uniformly and intimately by combining the active ingredient with liquid carriers and / or finely divided solid carriers, and then molding the product as needed.

Suitable formulations for oral administration are separate units (eg, capsules, caplets, cashiers, or tablets; powders or granules; aqueous solutions or each containing a predetermined amount of active ingredient. It can be indicated as a solution or suspension in a non-aqueous solution; or an oil-in-water emulsion or an aqueous emulsion in oil). This active ingredient may also be indicated as a bolus, lick or paste.

Tablets can be made by compressing or molding with one or more auxiliary components as needed. Compressed tablets, as needed, include binders (eg, povidone, gelatin, hydroxypropyl methylcellulose), lubricants, inert diluents, preservatives, disintegrants (eg, sodium starch glycolate, cross-linked povidone, cross-linked carboxy). It can be prepared by compressing the active ingredient in a free-flowing form (eg, powder or granule) mixed with sodium methylcellulose), a surfactant or a dispersant with a suitable machine. Molded tablets can be made by molding a mixture of powdered compounds moistened with an inert liquid diluent with a suitable machine. The tablets are coated or knurled as needed and, for example, cellulose ether derivatives (eg, hydroxypropyl methylcellulose) or methacrylate derivatives in varying ratios to provide the desired release profile. Can be formulated therein to provide sustained release or controlled release of the active ingredient. Tablets may optionally be provided with an enteric coating to provide release in parts of the intestine other than the stomach.

Suitable formulations for topical administration by mouth are lozenges containing the active ingredient in a gargle base (usually sucrose and acacia or tragacanth); inactive bases (eg gelatin and glycerin, or sucrose and acacia). ) Into sucrose tablets; as well as mouthwashes containing the active ingredient in a suitable liquid carrier. Formulations for rectal administration can be presented, for example, as suppositories with suitable bases containing cocoa butter or salicylate. Topical administration can also be by a percutaneous iontophoresis device.

Formulations suitable for vaginal administration may be presented as pessary, tampon, cream, gel, paste, foam or spray formulations containing, in addition to the active ingredient, carriers known in the art.

Formulations suitable for penile administration for prophylactic or therapeutic use include condoms, creams, gels, pastes, foams or sprays containing active ingredients as well as carriers known in the art. Can be shown as.

Pharmaceutical formulations suitable for rectal administration, in which the carrier is solid, can most preferably be indicated as a unit dose suppository. Suitable carriers include cocoa butter and other substances commonly used in the art. The suppository can be conveniently formed by mixing a softened or dissolved carrier with an active combination, followed by cooling and molding.

Suitable formulations for parenteral administration include: It may contain antioxidants, buffers, bacteriostats and solutes that make this formulation isotonic with the blood of the intended recipient. Aqueous and non-aqueous isotonic sterile injectable solutions; and aqueous and non-aqueous sterile suspensions, which may contain buffers and thickeners; and the compound is a blood component or one or more organs. A liposome or other particulate system designed to target. This formulation may be indicated in unit dose closed containers or multiple dose closed containers (eg ampoules and vials) and only requires the addition of sterile liquid carriers (eg water for injection) immediately prior to use. Can be stored in a lyophilized state. Immediate infusion solutions and infusion suspensions can be prepared from sterile powders, granules, and tablets of the above types.

An exemplary unit dose formulation is a formulation comprising a daily dose or daily partial dose of the active ingredient, or a suitable fraction thereof, as previously listed herein. In addition to the ingredients specifically mentioned above, it should be understood that the formulations of the present invention may include other agents conventional in the art in view of the type of formulation in question. For example, formulations suitable for oral administration may include additional agents such as sweeteners, thickeners and flavoring agents.

Compounds of the combinations of the present invention can be obtained in conventional manners known to those of skill in the art. Tenofovir disoproxil fumarate can be prepared, for example, as described in US Pat. No. 5,977,089. Methods for the preparation of FTC are described in WO 92/14743, which is incorporated herein by reference.

(Use of composition)
The compositions of the invention are administered to humans or other mammals in safe and effective amounts as described herein. These safe and effective amounts will vary depending on the type and size of mammal being treated and the desired treatment outcome. Any variety of methods known to those of skill in the art for packaging tablets, capsules, or other solid dosage forms suitable for oral administration that do not degrade the components of the invention are suitable for use in packaging. is there. This combination can be packed in glass and plastic bottles. Tablets, caplets, or other solid dosage forms suitable for oral administration may, if desired, be packed or included in various packaging materials containing desiccants (eg, silica gel). obtain. The packaging can be in the form of unit dose blister packaging. For example, the package may include one blister pack of tenofovir DF pills, tablets, caplets, or capsules, and another blister pack of emtricitabine pills, tablets, caplets, or capsules. The patient withdraws one dose (eg, pills) from one tray and one dose (eg, pills) from the other tray. Alternatively, the package may include a blister tray with a co-formulation combination of tenofovir DF and emtricitabine in a single pill, tablet, caplet, or capsule. As in other combinations and their packaging, the combinations of the invention include physiologically functional derivatives of tenofovir DF and FTC.

The packaging material may also have labeling and information related to the pharmaceutical composition printed on it. In addition, the manufactured article may include a booklet, a report, a note, a pamphlet, or a leaflet containing product information. This form of pharmaceutical information is referred to in the pharmaceutical industry as a "packaged publication". The packaged material may be attached to or included with the pharmaceutical product. This package listing and labeling of any manufactured article provides information related to the pharmaceutical composition. This information and labeling is available to health care professionals and patients and describes the composition, its dosage, and various other parameters required by regulatory agencies (eg, United States Food and Drug Agency). It provides various forms of information.

(Combination assay)
The combinations of the present invention are based on standard assays developed to test anti-HIV compounds (eg, WO 02/068058 and US Pat. No. 6,475,491) for in vitro activity and susceptibility to HIV, as well as laboratory-adapted cell lines ( For example, MT2) and peripheral blood mononuclear cells (PBMC) can be tested for cytotoxicity. Combination assays may be performed in varying concentrations of compounds of the combination may be determined and EC ₅₀ by serial dilutions.

(Example prescription)
The following examples further illustrate and demonstrate certain embodiments within the scope of the invention. Techniques and formulations are commonly found in Remington's Pharmaceutical Sciences (Mack Publishing Co., Easton, PA). Examples are given solely for illustration purposes and not to be construed as limitations, as many modifications can be made without departing from the spirit and scope of the invention. The following examples are intended for illustration purposes only and are not intended to limit the scope of the invention in any respect. The "active ingredient" refers to tenofovir disoproxil fumarate, emtricitabine, or a physiologically functional derivative of any of these.

(Tablet prescription)
The following exemplary formulations A, B, C, D, E, and F are wet-granulated with aqueous solutions, extragranular components are added, followed by magnesium stearate, and then compressed. Prepare by.

処方物Ｇ（制御放出処方物）：
この処方物を、水溶液を用いて成分を湿式顆粒化し、続いてステアリン酸マグネシウムを添加し、そして圧縮することによって調製する。

Prescription G (controlled release prescription):
The formulation is prepared by wet granulating the ingredients with aqueous solution, followed by addition of magnesium stearate and compression.

薬物放出は、約６〜８時間の期間に亘って起こり、そして１２時間後に完了する。

Drug release occurs over a period of about 6-8 hours and is complete after 12 hours.

(Capsule prescription)
Prescription H:
Capsule formulations are prepared by mixing the ingredients and filling them into two-part hard gelatin or hydroxypropyl methylcellulose capsules.

処方物Ｉ（制御放出カプセル剤）：
以下の制御放出カプセル剤処方物を、押出し機を用いて成分ａ、成分ｂ、および成分ｃを押出し、続いてこの押出し物を小球化（ｓｐｈｅｒｏｎｉｚａｔｉｏｎ）し、そして乾燥させることによって調製する。次いで、乾燥させたペレット剤を放出制御膜（ｄ）でコーティングし、そして２部構成の硬質ゼラチンまたはヒドロキシプロピルメチルセルロースカプセル中に充填することによって調製する。

Formulation I (Controlled Release Capsules):
The following controlled release capsule formulation is prepared by extruding component a, component b, and component c using an extruder, followed by spheronization of the extruded product and drying. The dried pellet is then prepared by coating with a release control membrane (d) and filling in two-part hard gelatin or hydroxypropyl methylcellulose capsules.

処方物Ｊ（経口用懸濁剤）：
活性成分を成分と混合し、そしてこれらを乾燥粉末として充填する。精製水を加え、そして使用前によく混合する。

Prescription J (oral suspension):
The active ingredients are mixed with the ingredients and filled as a dry powder. Add purified water and mix well before use.

処方物Ｋ（坐剤）：
Ｗｉｔｅｐｓｏｌ Ｈ１５の５分の１を、最高４５℃で、蒸気ジャケット型（ｓｔｅａｍ−ｊａｃｋｅｔｅｄ）のパンにおいて溶融する。活性成分を、２００ミクロンのふるいにかけて落とし、カッティングヘッドを取り付けたＳｉｌｖｅｒｓｏｎを用いて、なめらかな分散が達成されるまで、溶融した基剤に混合しながら加える。この混合物を４５℃に維持し、残存するＷｉｔｅｐｓｏｌ Ｈ１５を懸濁液に加え、そして均一な混合を確実にするように撹拌する。この完全な懸濁液を、２５０ミクロンのステンレススチール製ふるいを通過させ、そして撹拌を続けながら、４０℃まで冷却させる。３８℃〜４０℃の温度において、２．０２ｇの混合物を適切な２ｍｌのプラスチックの型に充填する。この坐剤を室温まで冷却させる。

Prescription K (suppository):
One-fifth of Witsol H15 is melted in a steam-jacketed pan at a maximum of 45 ° C. The active ingredient is sifted through a 200 micron sieve and added with a Silverson equipped with a cutting head, mixing with the molten base until smooth dispersion is achieved. The mixture is maintained at 45 ° C., the remaining Witessol H15 is added to the suspension and stirred to ensure uniform mixing. This complete suspension is passed through a 250 micron stainless steel sieve and allowed to cool to 40 ° C. with continued stirring. At a temperature of 38 ° C to 40 ° C, 2.02 g of the mixture is filled into a suitable 2 ml plastic mold. Allow the suppository to cool to room temperature.

（一定用量の組み合わせ錠剤）
フマル酸テノホビルジソプロキシル（ＴＤＦ）３００ｍｇ／エムトリシタビン２００ｍｇの一定用量の組み合わせ錠剤を、従来の方法を用いて、湿式顆粒化／流体床乾燥プロセスを用いて処方した。米国特許第５９３５９４６号；Ｌ．Ｙｏｕｎｇ（編集者）．Ｔａｂｌｅｔｉｎｇ Ｓｐｅｃｉｆｉｃａｔｉｏｎ Ｍａｎｕａｌ第５版，Ａｍｅｒｉｃａｎ Ｐｈａｒｍａｃｅｕｔｉｃａｌ Ａｓｓｏｃｉａｔｉｏｎ，Ｗａｓｈｉｎｇｔｏｎ，ＤＣ，（２００１）；Ｌ．Ｌａｃｈｍａｎ，Ｈ．Ｌｉｅｂｅｒｍａｎ（編集者）．Ｐｈａｒｍａｃｅｕｔｉｃａｌ Ｄｏｓａｇｅ Ｆｏｒｍｓ：Ｔａｂｌｅｔｓ（第２巻），Ｍａｒｃｅｌ Ｄｅｋｋｅｒ Ｉｎｃ．，Ｎｅｗ Ｙｏｒｋ，１８５−２０２（１９８１）；Ｊ．Ｔ．ＦｅｌｌおよびＪ．Ｍ．Ｎｅｗｔｏｎ，Ｊ．Ｐｈａｒｍ．Ｐｈａｒｍａｃｏｌ．２０，６５７−６５９（１９６８）；ＵＳ Ｐｈａｒｍａｃｏｐｅｉａ ２４−Ｎａｔｉｏｎａｌ Ｆｏｒｍｕｌａｒｙ １９，「Ｔａｂｌｅｔ Ｆｒｉａｂｉｌｉｔｙ」，第＜１２１６＞章，２１４８頁（２０００）を参照のこと。

(Constant dose combination tablet)
A constant dose combination tablet of tenofovir disoproxil (TDF) 300 mg / emtricitabine 200 mg fumarate was formulated using conventional methods and using a wet granulation / fluid bed drying process. U.S. Pat. No. 5,935946; Young (editor). Tableting Specialization Manual, 5th Edition, American Pharmacists Association, Washington, DC, (2001); L. et al. Lachman, H. et al. Lieberman (Editor). Pharmaceutical Dose Forms: Tablets (Volume 2), Marcel Dekker Inc. , New York, 185-202 (1981); J. Mol. T. Fell and J.M. M. Newton, J. et al. Pharm. Pharmacol. 20, 657-659 (1968); US Pharmacopoeia 24-National Formulary 19, "Tablet Friability," Chapter <1216>, p. 2148 (2000).

The effect of the water level of the granules (in the range of 40 w / w% to 50 w / w%) and the effect of the wet massing time, the physicochemical properties of the final powder blend, as well as the uniformity and compression of the blend. The study was based on its performance with respect to rate (tablet compressibility). In addition, content uniformity, assay, stability and dissolution performance were evaluated for tablets in a fixed dose combination of TDF / emtricitabine.

(Prescription device)
The device was equipped with a high shear mixer with a pressure tank for adding granulated water and a spray nozzle tip, a fluid bed dryer, a mill, a tumble blender, a rotary tablet press, and a tablet deduster.

(Prescription process)
The dried ground powder was blended with extragranular microcrystalline cellulose and sodium croscarmellose and then with magnesium stearate. The powder sample was taken out after mixing with magnesium stearate. This blend sample was evaluated for bulk density, mesh analysis and compressibility. This powder blend mixed with magnesium stearate was compressed into tablets by a press facility (setup).

(material)
Table 1 below lists the quantitative composition of TDF / emtricitabine tablet formulations.

（特性評価装置）
水分含量を、加熱ランプ／天秤系を用いて乾燥の際の重量減少によって測定した。粉末ブレンドを、チャンバーを装着したサンプリングシーフを用いてサンプリングし、粉末ブレンドの均一性を決定した。二組のサンプルを、ブレンダーにおけるいくつかの場所の各々から取り出した。ブレンドの均一性の分析を、各場所由来の１つのサンプルについて行った。

(Characteristic evaluation device)
Moisture content was measured by weight loss during drying using a heating lamp / balance system. The powder blend was sampled using a sampling thief equipped with a chamber to determine the uniformity of the powder blend. Two sets of samples were taken from each of several locations in the blender. Analysis of blend uniformity was performed on one sample from each location.

Particle size analysis of the final powder blend was determined by sieving multiple gram samples through a screen using a sonic shifter. The amount of final powder blend retained in each sieve and fine collector was determined by calculating the difference in weight between the sieve and fine collector before and after the test. The geometric mean diameter particle size was calculated by logarithmic weighting of the sifted distribution.

The bulk density was determined by filling the graduated cylinder with the final powder blend and measuring the difference in weight per unit volume between the empty graduated cylinder and the filled graduated cylinder.

The tablets were characterized for crushability using a friavirator, a hardness tester, a thickness makelometer equipped with a printing press, and a weight balance.

The compression index was determined using a rotary tablet press with a flat, rounded edge punch for a target weight of 400 mg. The powder blend was compressed using a target upper punch pressure in the range of about 100 MPa to 250 MPa. Apparent normalized firing power was determined and normalized for tablet thickness and diameter.

Tablet hardness was determined using a hardness tester. Tablet thickness was determined using a micrometer and tablet weight was determined using a loading balance.

(Wet granulation)
The powder was blended with a granulator and then granulated with water. Impeller and chopper speeds were kept constant in the blender at low settings during the granulation and wet agglomeration operations. After the addition of water, the impeller and chopper were stopped, the granulator balls were opened and the granulation consistency and texture were observed. The lid was closed and a wet agglomeration step was performed. The acceptable granules had 40 w / w% and 60 w / w% water, respectively.

(Wet milling)
Each wet granule was agglomerated using a mill equipped with a screen and an impeller to facilitate a uniform drying process. The ground wet granules were loaded into a fluid bed dryer immediately after wet milling.

(Fluid bed drying)
The ground wet granules were dried using an inlet air set temperature of about 70 ° C. and an air flow of about 100 cfm. The target LOD was about 1.0% with a range of 1.5% or less (not more than NMT). The total fluid bed drying time was in the range of 53-75 minutes. The final LOD was in the range of 0.4% to 0.7% for all dry batches. The final exhaust temperature for all batches was in the range of 47 ° C to 50 ° C.

(Dry milling)
All dried granules were ground through a perforated screen. The mill was equipped with and operated a square impeller. Lots were ground and manually transferred to a V-blender.

(blend)
Each lot was blended using a V-blender. In one set of three formulations, starting with 12 kg of material, the yield of the final powder blend available for compression after blending is from 10.5 kg (87.5%). It was in the range of 11.1 kg (92.5%). The bulk density of the final powder blend was in the range of 0.48 g / cc to 0.58 g / cc, and the geometric mean diameter particle size was in the range of 112 μm to 221 μm. Water percentage and wet agglomeration time affect the particle size and bulk density of the final powder blend.

The powder blend for both tenofovir DF and emtricitabine gives the average (n = 10) intensity values for tenofovir DF in the range of 100.6% to 102.8% of the target intensity for the lot and the relative standard deviation (RSD). ) Was 0.5% to 1.7%. Mean (n = 10) intensity values for emtricitabine range from 101.3% to 104.1% of the target intensity for lots, with relative standard deviation (RSD) of 0.6% to 1.7%. It was in range. Moisture levels in the final powder blend ranged from 0.8% to 1.1% LOD.

(Tablet compression)
The final blend was compressed using a rotary tablet press and the tablets were film coated.

Three 300 g formulations (Table 2) were granulated with a granulator equipped with 1 L balls. The amount of ingredients in the granules was based on a total batch size of 300 g. The formulations in lots 1 and 2 differed in the amount of microcrystalline cellulose of 30 w / w% vs. 20 w / w%, respectively. Lot 2 and Lot 3 were identical except for the type of binder. Lot 2 contained 5 w / w% gelatinized starch as a binder and Lot 3 contained 5 w / w% povidone as a binder.

水の添加の後、インペラーおよびチョッパーを停止し、そしてグラニュレーターボールを開き、顆粒コンシステンシーおよび顆粒組織を観察した。類似の顆粒コンシステンシーを達成するために、ロット１、ロット２、およびロット３を、それぞれ、４５ｗ／ｗ％、４０ｗ／ｗ％、および３０ｗ／ｗ％の水を用いて顆粒化した。蓋を閉め、そして湿式塊状化段階を行った。全てのロットで３０秒の湿式塊状化をし、受容可能な顆粒を得た。全てのバッチからの湿潤顆粒は、ふるいを通してハンドスクリーンし、脱塊状化した。得られた顆粒を、６０℃に設定された対流オーブンで約２０時間トレー乾燥し、ＬＯＤは１．０％未満となった。全てのバッチからの乾燥した顆粒を、ふるいを通してハンドスクリーンした。この顆粒を小スケール（３００ｍＬ）Ｖ−ブレンダーに適合させるために、最終的なブレンドバッチサイズを１００ｇに調整した。一部分である、ロット１からの８１ｇの生じたブレンドを、１５ｇの微結晶性セルロースと、３ｇのクロスカルメロースナトリウムと、１ｇのステアリン酸マグネシウムと混合した。ロット２およびロット３からの８６ｇの生じた顆粒を、１０ｇの微結晶性セルロースと、３ｇのクロスカルメロースナトリウムと、１ｇのステアリン酸マグネシウムと各々ブレンドした。

After the addition of water, the impeller and chopper were stopped and the granulator balls were opened and the granule consistency and texture were observed. To achieve similar granule consistency, lots 1, 2 and 3 were granulated with 45 w / w%, 40 w / w% and 30 w / w% water, respectively. The lid was closed and a wet agglomeration step was performed. All lots were wet agglomerated for 30 seconds to give acceptable granules. Wet granules from all batches were hand screened through a sieve and agglomerated. The obtained granules were tray-dried in a convection oven set at 60 ° C. for about 20 hours, and the LOD was less than 1.0%. Dried granules from all batches were hand screened through a sieve. The final blend batch size was adjusted to 100 g to fit the granules to a small scale (300 mL) V-blender. A portion, 81 g of the resulting blend from Lot 1, was mixed with 15 g of microcrystalline cellulose, 3 g of croscarmellose sodium and 1 g of magnesium stearate. 86 g of the resulting granules from Lot 2 and Lot 3 were blended with 10 g of microcrystalline cellulose, 3 g of sodium croscarmellose and 1 g of magnesium stearate, respectively.

Purity analysis was performed by reverse phase HPLC (High Performance Liquid Chromatography). Tenofovir disoproxil fumarate and emtricitabine-related impurities were characterized and measured in bulk APIs (active pharmaceutical ingredients) prior to formulation in the three lots of Table 2 and in tablets produced after formulation. It was characterized and measured again. This impurity contains by-products derived from the hydrolysis of the extracellular amino groups of tenofovir disoproxil fumarate and emtricitabine, as well as the hydrolysis of the disoproxil (POC) ester of tenofovir disoproxil fumarate. In each lot, the total impurities associated with tenofovir disoproxil fumarate and emtricitabine were less than 1% after formulation and tablet production.

The physicochemical properties of tenofovir disoproxil fumarate and emtricitabine tablets were evaluated by appearance, water content, label strength, impurities and degradable organism content, and tablet lysis. Stability studies were performed on drug products packaged in intended clinical container closure systems and container closure systems that are identical to commercially available container closure systems. There were no signs of discoloration or tablet coarsening during the course of the stability study. Film-coated tenofovir disoproxil fumarate and emtricitabine tablets are packaged with a silica gel desiccant and have satisfactory stability at 40 ° C./75% RH (relative humidity) for up to 6 months. showed that. A significant reduction in% label strength of tenofovir DF or emtricitabine (defined as degradation of 5% or greater) is not observed after 6 months at 40 ° C./75% RH when packaged and stored with a desiccant. It was. The increase in total degradation products was packaged with 3 g desiccant and stored at 40 ° C./75% RH after 6 months, 1.5% for tenofovir DF, and 0.6 for emtricitabine. It was% to 0.7%.

All publications and patent applications listed herein are for reference only to the extent that each individual publication or patent application is shown in detail and individually as reference. It will be used.

Although certain embodiments are described in detail above, one of ordinary skill in the art will clearly understand that many changes can be made within the scope of the claims without departing from the teachings. All such modifications are intended to be included within the claims of the present invention.

(Embodiment of the present invention)
(A1)
The following formula for effective quantities:

の化合物、またはその生理学的に機能的な誘導体を、有効量の以下の式：

Compounds, or physiologically functional derivatives thereof, in effective amounts according to the following formula:

の化合物および薬学的に受容可能なキャリアと組み合わせて含む薬学的組成物またはその生理学的に機能的な誘導体であって、
ここで、Ｒ^１およびＲ^２は、独立して、Ｈ、Ｃ_１〜Ｃ_６アルキル、Ｃ_１〜Ｃ_６置換アルキル、Ｃ_６〜Ｃ_２０アリール、Ｃ_６〜Ｃ_２０置換アリール、Ｃ_６〜Ｃ_２０アリールアルキル、Ｃ_６〜Ｃ_２０置換アリールアルキル、アシルオキシメチルエステル−ＣＨ_２ＯＣ（＝Ｏ）Ｒ^９、およびアシルオキシメチルカルボネート−ＣＨ_２ＯＣ（＝Ｏ）ＯＲ^９から選択され、ここでＲ^９は、Ｃ_ｌ〜Ｃ_６アルキル、Ｃ_ｌ〜Ｃ_６置換アルキル、Ｃ_６〜Ｃ_２０アリールおよびＣ_６〜Ｃ_２０置換アリールであり；
Ｒ^３は、Ｈ、Ｃ_ｌ〜Ｃ_６アルキル、Ｃ_ｌ〜Ｃ_６置換アルキル、またはＣＨ_２ＯＲ^８から選択され、ここでＲ^８は、Ｃ_ｌ〜Ｃ_６アルキル、Ｃ_ｌ〜Ｃ_６ヒドロキシアルキル、およびＣ_ｌ〜Ｃ_６ハロアルキルであり；
Ｒ^４およびＲ^５は、独立して、Ｈ、ＮＨ_２、ＮＨＲおよびＮＲ_２から選択され、ここでＲは、Ｃ_ｌ〜Ｃ_６アルキルであり；そして
Ｒ^６およびＲ^７は、独立して、ＨおよびＣ_ｌ〜Ｃ_６アルキルから選択され；
ここで、Ｂは、アデニン、グアニン、シトシン、ウラシル、チミン、７−デアザアデニン、７−デアザグアニン、７−デアザ−８−アザグアニン、７−デアザ−８−アザアデニン、イノシン、ネブラリン、ニトロピロール、ニトロインドール、２−アミノプリン、２−アミノ−６−クロロプリン、２，６−ジアミノプリン、ヒポキサチン、シュードウリジン、５−フルオロシトシン、５−クロロシトシン、５−ブロモシトシン、５−ヨードシトシン、シュードシトシン、シュードイソシトシン、５−プロピニルシトシン、イソシトシン、イソグアニン、７−デアザグアニン、２−チオピリミジン、６−チオグアニン、４−チオチミン、４−チオウラシル、Ｏ^６−メチルグアニン、Ｎ^６−メチルアデニン、Ｏ^４−メチルチミン、５，６−ジヒドロチミン、５，６−ジヒドロウラシル、４−メチルインドール、およびピラゾロ［３，４−Ｄ］ピリミジンから選択され；そして
Ｒは、Ｈ、Ｃ_ｌ〜Ｃ_ｌ８アルキル、Ｃ_ｌ〜Ｃ_１８置換アルキル、Ｃ_２〜Ｃ_ｌ８アルケニル、Ｃ_２〜Ｃ_ｌ８置換アルケニル、Ｃ_２〜Ｃ_ｌ８アルキニル、Ｃ_２〜Ｃ_ｌ８置換アルキニル、Ｃ_６〜Ｃ_２０アリール、Ｃ_６〜Ｃ_２０置換アリール、Ｃ_２〜Ｃ_２０複素環、Ｃ_２〜Ｃ_２０置換複素環、ホスホネート、ホスホホスホネート、ジホスホホスホネート、ホスフェート、ジホスフェート、トリホスフェート、ポリエチレンオキシから選択される、
組成物。

A pharmaceutical composition or a physiologically functional derivative thereof comprising in combination with a compound of the above and a pharmaceutically acceptable carrier.
Here, R ¹ and R ² are independently H, C _{1 to} C ₆ alkyl, C _{1 to} C ₆ substituted alkyl, C _{6 to} C ₂₀ aryl, C _{6 to} C ₂₀ substituted aryl, C ₆ to C. ₂₀ arylalkyl, C _{6 to} C _20- substituted arylalkyl, acyloxymethyl ester-CH ₂ OC (= O) R ⁹ , and acyloxymethyl carbonate-CH ₂ OC (= O) OR ⁹ selected here, R ⁹ Are C _{l to} C ₆ alkyl, C _{l to} C ₆ substituted alkyl, C _{6 to} C ₂₀ aryl and C _{6 to} C ₂₀ substituted aryl;
R ³ is selected from H, C _{l to} C ₆ alkyl, C _{l to} C ₆ substituted alkyl, or CH ₂ OR ⁸ , where R ⁸ is C _{l to} C ₆ alkyl, C _{l to} C ₆ hydroxyalkyl. , And C _{l to} C ₆ haloalkyl;
R ⁴ and R ⁵ are independently selected from H, NH ₂ , NHR and NR ₂ , where R is _{Cl to} C ₆ alkyl; and R ⁶ and R ⁷ are independent. Selected from H and C _{l to} C ₆ alkyl;
Here, B is adenine, guanine, cytosine, uracil, timidine, 7-deazaadenine, 7-deazaguanin, 7-deaza-8-azaguanine, 7-deaza-8-azaadenine, cytosine, nebulin, nitropyrrole, nitroindole, 2-aminopurine, 2-amino-6-chloropurine, 2,6-diaminopurine, hypoxatin, pseudouridine, 5-fluorocytosine, 5-chlorocytosine, 5-bromocytosine, 5-iodocytosine, pseudocytosine, pseudo isocytosine, 5-propynyl cytosine, isocytosine, isoguanine, 7-deazaguanine, 2-thiopyrimidine, 6-thioguanine, 4-thiothymine, 4-thiouracil, ^{O 6} - methylguanine, ^{N 6} - methyl adenine, ^{O 4} - methylthymine, Selected from 5,6-dihydrotimine, 5,6-dihydrouracil, 4-methylindole, and pyrazolo [3,4-D] pyrimidines; and R is H, C _{l to} C _l8 alkyl, C _l to C. _18- substituted alkyl, C _2- C _l8 alkenyl, C _2- C _l8 substituted alkenyl, C _2- C _l8 alkynyl, C _2- C _l8 substituted alkynyl, C _6- C ₂₀ aryl, C _6- C ₂₀ substituted aryl, C Selected from _{2 to} C ₂₀ heterocycles, C _{2 to} C ₂₀ substituted heterocycles, phosphonates, phosphophosphonates, diphosphophosphonates, phosphates, diphosphates, triphosphates, polyethyleneoxy,
Composition.

(B2)
In the composition of Embodiment A1, in Formula 1, R ¹ and R ² are independently H, C _{l to} C ₆ alkyl, C _{l to} C ₆ substituted alkyl, C _{6 to} C ₂₀ aryl, C. _{6 to} C _20- substituted aryl, C _{6 to} C ₂₀ arylalkyl, C _{6 to} C _20- substituted arylalkyl, acyloxymethyl ester-CH ₂ OC (= O) R ⁹ , and acyloxymethyl carbonate-CH ₂ OC (= O) ) Selected from OR ⁹ , where R ⁹ is C _{l to} C ₆ alkyl, C _{l to} C ₆ substituted alkyl, C _{6 to} C ₂₀ aryl and C _{6 to} C ₂₀ substituted aryl; and R ³ , R. ^A composition in which ⁴ , R ⁵ , R ⁶ , and R ⁷ are independently H or C _{l to} C ₆ alkyl.

(C3)
A composition of embodiment A1, wherein in formula 2 B is cytosine or 5-halocytosine.

(D4)
In the composition of Embodiment A1, in Formula 1, R ¹ and R ² are independently H, C _{l to} C ₆ alkyl, C _{l to} C ₆ substituted alkyl, C _{6 to} C ₂₀ aryl, C. _{6 to} C _20- substituted aryl, C _{6 to} C ₂₀ arylalkyl, C _{6 to} C _20- substituted arylalkyl, acyloxymethyl ester-CH ₂ OC (= O) R ⁹ , and acyloxymethyl carbonate-CH ₂ OC (= O) ) Selected from OR ⁹ , where R ⁹ is C _{l to} C ₆ alkyl, C _{l to} C ₆ substituted alkyl, C _{6 to} C ₂₀ aryl and C _{6 to} C ₂₀ substituted aryl; and R ³ , R. ^A composition in which ⁴ , R ⁵ , R ⁶ , and R ⁷ are independently H or C _{l to} C ₆ alkyl; and in formula 2, B is cytosine or 5-halositocin.

(E5)
In the composition of embodiment D4, in formula 1, R ¹ and R ² are independently H, acyloxymethyl ester-CH ₂ OC (= O) R ⁹ and acyloxymethyl carbonate-CH ₂ OC ( = O) Selected from OR ⁹ , where R ⁹ is C _{l to} C ₆ alkyl; and R ³ , R ⁴ , R ⁵ , R ⁶ , and R ⁷ are independently H or C _l. ~ C ₆ alkyl; and in formula 2, B is cytosine or 5-halocytosine and R is H, the composition.

(F6)
In the composition of embodiment E5, in formula 1, R ₁ and R ₂ are independently selected from H and −CH ₂ OC (= O) OCH (CH ₃ ) ₂ ; R ³ is − CH ₃ ; and R ⁴ , R ⁵ , R ⁶ , and R ⁷ are H; and in formula 2, B is 5-fluorocytosine and R is H, a composition.

(G7)
A pharmaceutical composition in which a pharmaceutically effective amount of [2- (6-amino-purine-9-yl) -1-methyl-ethoxymethyl] -phosphonate diisopropoxycarbonyloxymethyl ester fumarate (fumal) Tenofovir disoproxil acid) or a physiologically functional derivative thereof, and a pharmaceutically effective amount of (2R, 5S,) -4-amino-5-fluoro-1- (2-hydroxymethyl-1,3-). A composition comprising oxathiolan-5-yl)-(1H) -pyrimidine-2-one (emtricitabine) or a physiologically functional derivative thereof; as well as a pharmaceutically acceptable carrier.

(H8)
A third pharmaceutical formulation of embodiments A1-G7 selected from the group consisting of protease inhibitors, nucleoside reverse transcriptase inhibitors or nucleotide reverse transcriptase inhibitors, non-nucleoside reverse transcriptase inhibitors, and integrase inhibitors. A formulation that further comprises an active ingredient.

(I9)
Pharmaceutical formulations of embodiments A1-H8 in unit dosage form.

(J10)
A method for treating or preventing the symptoms or effects of HIV infection in an infected animal, comprising the step of administering to the animal the pharmaceutical compositions of embodiments A1-I9.

Claims (1)

The inventions described herein.